IE74202B1 - 4,5,6-substituted-2-pyrimidinamines - Google Patents

4,5,6-substituted-2-pyrimidinamines

Info

Publication number
IE74202B1
IE74202B1 IE7487A IE7487A IE74202B1 IE 74202 B1 IE74202 B1 IE 74202B1 IE 7487 A IE7487 A IE 7487A IE 7487 A IE7487 A IE 7487A IE 74202 B1 IE74202 B1 IE 74202B1
Authority
IE
Ireland
Prior art keywords
pyridinyl
pyrimidinamine
phenyl
methyl
benzenediamine
Prior art date
Application number
IE7487A
Other versions
IE870074L (en
Inventor
Lawrence Wayne Torley
Bernhard B Johnson
John Paul Dusza
Original Assignee
American Cyanamid Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=25224278&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IE74202(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of IE870074L publication Critical patent/IE870074L/en
Publication of IE74202B1 publication Critical patent/IE74202B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

This disclosure describes novel 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines having anti-asthmatic activity.

Description

This invention relates to organic compounds and, more particularly, is concerned with 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines having anti-asthmatic activity which may be represented by the following structural formula: «3 wherein is hydrogen, alkyl (CpC^) , -COCO2C2H5 or N,N-dimethylaminoethyl; is mono- or poly-substituted phenyi wherein the substituents >are alkyl(C^-C^), alkoxyCC^-C^), -210 chloro, bromo, trifluoromethyl, hydroxy, phenyl, amino, monoalkyl-(Ci-Cg)amino, dialkyl (Cj-C^)amino, alkyl(Ci"C3)keto, propenyloxy, carboxyl, oxyacetic acid, oxyacetic acid ethyl ester, sulfamilamido, NjN-dialkylCC^-C^Jsulfamilamido, N-methylpiperazinyl, piperidinyl, lH-imidazol-1yl, ΙΗ-triazol-l-yl, ΙΗ-benzimidazol -z-yl, 1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or moieties of the formula: 0 R (I U , · / -CO R, -NH-C-R, -NR-C-R, -O^CH^n-N^ , R NHCHO N-OH N-OCH. II /11/(/3 -C-NH-(CH2)n-N^ , -CH-CH3,C-CH3, -C-CH3, -(CH2)m-R7, -X-(CH2)m-R7 and -X-CH^-C-N N-Rft wherein R is alkyl(C^-C^, X is oxygen (-0-) or sulfur (-S-), m is 1-3, n is 2 or 3, Rg is hydrogen, alkyl(C^-C3), alkoxy (C^-C^),chloro, bromo, iodo or trifluoromethyl, R? is 1H-imidazol-l-yl or morpholino and Rg is alkyl(C^-C^), phenyl or monosubstituted phenyl wherein the substituents are alkyl (Cj-C3), halogen or trifluoromethyl; R3 is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl, 2-furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 2-pyrazinyl, 2-benzofuranyl, 2-(pyridine-N-oxide), 3-(pyridine-N-oxide), 4-(pyridine-N-oxide), lH-indol-2-yl, lH-indol-3-yl, l-methyl-lH-pyrroI-2-yl, 4-quinolinyl, 4-pyri-dinyl methyl iodide, dimethylaminophenyl or N-acetyl-N-methylaminophenyl; R^ is hydrogen or alkyl(C^-C3); and R^ is hydrogen or alkyl(C^-C^); and the pharmacologically acceptable acid-addition salts thereof. -310 The present invention also icludes novel compositions of matter containing the above-defined compounds which are useful for treating asthma, allergic diseases, i n f 1ammation and diabetes in mammals. The invention also comprises processes of preparing the compounds within the scope of the above formula.
Non-prepublished EP-A-210 044 discloses 2-Ami‘no-4-subst.-5(hydroxy or alkoxy)pyrimidines useful for the treatment of pulmonary, inflammatory, allergic and cardiovascular diseases.
DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention are obtainable as crystalline materials having characteristic melting points and absorption spectra. They are in general sparingly soluble in organic solvents such as lower alkanols, chloroform, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, acetone and the like, but are generally insoluble in water.
The novel A, 5,6-substituted-2-pyrimidinamines of the present invention in general may be prepared as set forth in the following reaction schemes.
Scheme I (Lower |5 (Lower 9 ?* rJUh2 A"~r>2_ e3-8J«-N(JS5S«D2 Δ wherein R^, » ^3’ % an^ R·^3*3 3S hereinabove defined.
In accordance with Scheme I, a heteroaryl (R^) alkanoyl (R^) compound 1, e.g 2-acetylpyridine, 2-acetyl-45 furan, 3-acetylthiophene, 2-acetyl-6-methylpyridine, 2propionyl pyridine or 3-propionyl pyridine and the like, f is reacted with a di(lower alkyl)-formamide or acetamide di(lower alkyl) acetal 2, e.g; Ν,Ν-dimethylformamide » dimethylacetai or N,N-dimethylacetamide dimethylacetal at an elevated temperature in the range of about 50°C.to about 150°C.for from about 4 to 24 hours to produce the 3-di( lower alkyl laminoacrylophenone 3. The acrylophenone 3 is then reacted with an appropriately substituted phenylguanidine (R^HR?), 4 as the base or as the carbo15 nate, sulfate, nitrate, hydrochloride or dihydrochloride salt in an inert solvent such as absolute ethanol, npropanol, isopropyl alcohol or 2-methoxyethanol and the like, by heating at the reflux temperature for from 6-48 hours. The product 5 is separated by the partial evapora20 tion of the solvent, then cooling and collected and recrystallized in a conventional manner from solvents such as n-propyl alcohol, isopropyl alcohol, absolute ethyl alcohol or 2-methoxyethanol and the like and combinations of solvents such as chloroform/hexane, dichoromethane/25 hexane or isopropyl alcohol/ethylene glycol monomethyl ether and the like.
Scheme II Or Olchloromethane Mineral Acid H2S04 HC1 HNO3 H3PO4 -5wherein R. , R_, Rn, R. and Rr are as hereinabove defind. 3 4 5 In accordance with Scheme II, when the 4,5,6substituted- 2-pyrimidinamine product _5 is dissolved by heating in a solvent such as absolute ethanol, isopropyl alcohol or dichloromethane, then stirred at room temperature and reacted with a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid and the like, dissolved in absolute ethanol or isopropyl alcohol and the like, the 4,5,6-substituted-2-pyrimidinamine acid addition salt _6 is precipitated on standing for 30 minutes and chilling for several hours.
Alternatively, acid addition salts· may be formed with organic acidds such as citric acid or maleic acid and the like by dissolving the desired 4,5,o-substituted-2pyrimidinamine in hot, absolute ethanol or 2-methoxyethanol in the presence of the organic acid. Cooling provides the desired compounds as solids.
The novel compounds of the present invention are highly active as antiasthmatic and antiallergic agents as will be demonstrated hereinbelow.
The bronchospasm of allergic asthma is a consequence of the release of mediators, such as histamine and slow-reacting substances from masts cells. The role of mediator release in the induction of an asthmatic attack has been fully reviewed and documented; see Kaliner, M. and Austen, K. F., Bronchial Asthma Mechanisms and Therepautics, E. B. Weiss, Editor, Little, Brown and Company, Boston, 163, (1976); Lichtenstein, L. M-, Asthma-Physiology, Immunopharmacology and Treatment, Second International Symposium, L. M. Lichtenstein and K.
F. Austen, Editors, Academic Press, New York, 51, (1979); and Bell, S. C., et al., Annual Reports in Medicinal Chemistry, 14, 51, H. J. Hess, Editor, Academic Press, New York, (1979).
The novel compounds of this invention have been tested by the procedure of Lichtenstein, L. M. and Osler, A. G., J. Exp. Med., 120, 507-530 (1964), which evaluates -65 the ability of compounds to inhibit mediator (histamine) release from immunologically stimulated human basophils.
* Reagents IPX Concentrated Tris Buffer * Dissolve 140.3 g of sodium chloride, 7.45 g of Trizma-Tris Pre-Set, Reagent Grade, pH 7.6, at 25°C (Sigma Chemical Co.) in sufficient water to give a final volume of 2 liters.
Human Albumin (Sigma Chemical Co.) (30 mg/ml) Calcium and Magnesium Stocks Made to 0.075 M 0.5 M respectively, with calcium chloride dihydrate and magnesium chloride hexahydrate. Tris-A Buffer A 10 ml portion of 10X Tris Buffer and 1.0 ml of 20 human albumin are diluted to 100 ml with water.
Tris ACM Buffer A 10 ml portion of 10X Tris Buffer, 1.0 ml of human albumin, 0.8 ml of calcium stock and 0.2 ml of magnesium stock are diluted to 100 ml with water.
Rabbit Antihuman IgE Behring Diagnostics (Generally used at 10 yg protein/ml final concentration).
House Dust Mite Extract (Dermatophagoides Farinae) Strength 1:100 (w:v, allergenic extract, Hollister—Stier Labs. Generally this is diluted 1:1000 to 1:10,000 (considering the vial as stock).
Other Allergens Interdermal solutions or intramuscular preparations for hyposensitization, Hollister-Steir Labs. The final concentration used is on the order of 1 PNU/ml.
Separation of Leukocytes from Human Blood and Challenge Eighty milliliters of blood is withdrawn from subjects with known histamine release to anti-IgE, ragweed antigen or other specific allergen, using four 20 ml heparinized tubes. This 80 ml of blood is mixed with -75 20 ml of saline containing 0.6 g of dextrose and 1.2 g of dextran. The blood is allowed to sediment at room temperature in two 50 ml polycarbonate centrifuge tubes until a sharp interface develops between the red cells and plasma « (60-90 minutes). The plasma (top) layer from each tube is withdrawn by pipet and transferred to respective 50 ml > polycarbonate tubes. The plasma is centrifuged for 8 minutes at 110X G at 4°C. The supernatant is carefully poured off as completely as possible and the cell button is resuspended in 2-3 ml of Tris-A buffer using a sili15 conized Pasteur pipet. The resuspension is accomplished by drawing the liquid gently in an out of the pipet, with the tip below the liquid until an even suspension of cells is obtained. Sufficient Tris-A buffer is then added to bring the volume in the tube to about 45 ml and the tube is centrifuged at 110X G for 8 minutes at 4Oc. The supernatant is poured off and the cell button is resuspended and centrifuged as described above. The supernatant is poured off and the cell button is suspended in 2-3 ml of Tris-ACM buffer to make the final volume sufficient to allow addition to the reaction tubes.
Reaction tubes containing anti-IgE or antigens, either alone or with test compound in a total volume of 0.2 ml are prepared and placed in a 37°C bath. The cells are warmed to 37°C and frequently swirled to ensure an even suspension, while 1.0 ml aliquots are added to each reaction tube. The tubes are then incubated for 60 minutes at 37°c, vortexing the tubes gently every 15 minutes to keep the cells evenly suspended. When the reaction is complete, the tubes are centrifuged at 4°C for 10 minutes 3$ at 1500 rpm to sediment the cells. One ml aliquots of supernatant are transferred to 12 mm by 75 mm polyethylene tubes and 0.2 ml of 8% perchloric acid is added to each . tube. Blanks and totals are included in each test. The blanks have cells and all reagents except antigen or anti- κ IgE- The totals contain 0.24 ml of 8% perchloric acid, one ml of cells and 0.2 ml of buffer.. All samples are -85 then centrifuged to remove the precipitate protein.
Assay of Released Histamine by the Automated Fluorometric Method This automated method has been described by Siraganian, R. P., in Anal. Biochem., 57, 383 (1974) and J. Immunol. Methods, T_, 283 (1975) and is based on the manual method of Shore, P. A-, et al., J. Pharmacol. Exp. Ther., 217, 182 (1959).
The automated system consists of the following Technicon Autoanalyzer II components: Sampler IV, Dual15 Speed Proportioning Pump III, Fluoronephelometer with a narrow pass primary filter 7-60 and a secondary filter 3-74, Recorder, and Digital Printer. The manifold used is the one described by Siraganian vide supra, with the following modifications: the dialyzer is omitted; all pumping tubes pass through a single proportioning pump with large capacity and twice the volume of sample is taken for anaylsis.
The automated chemistry consists of the following steps: Extraction from alkaline saline into butanol, back extraction into dilute hydrochloric acid by addition of heptane, reaction of histamine with o-phthaldialdehyde (OPT) at high pH and conversion of the OPT adduct to a stable fluorophore with phosphoric acid. The reaction product is then passed through the fluorometer. The full scale response is adjusted to 50 ng histamine base with a threshold sensitivity of approximately 0.5 ng.
Calculation of the Results of Histamine Release Tests The instrument blank (wash) is substracted from the ng histamine of each sample. Then the ng histamine of each sample is divided by the mean of the three totals (cells lysed with perchloric acid) to obtain percent release.
Control samples contain antigen but no test compound. Blank (or spontaneous release) samples contain neither antigen nor test compound. The mean of the blanks -9(three replicates) is subtracted from the percent release for controls and test compounds.
The means for control and test compound groups are computed and the result for a test compound is computed as percent of control by the formula: % Histamine Release with Test Compound 100 X --% Histamine Release in Controls Values obtained at different concentrations of test compound are used to calculate an IC50 (the concentration in μΜ which causes a 50% inhibition of histamine release) by linear regression. A compound is considered active if the IC5Q is £48 μΜ.
The results of this test on typical compounds of this invention appear in Table I. -10TABLE I Inhibition of Histamine Release from Immunologically Stimulated Human Basophils Compound 1 IC50(yM) 4-(2-Furanyl)-5-methyl-N-phenyl-2-pyrimidinamine 17.7 4-( 4-Pyridinyl)-N-( (3-trifluoromethyl)phenyl ]2-pyrimidinamine 32.0 N-(4-Methoxyphenyl)-4-(3-pyridinyl)-2pyrimidinamine 1.4 N-Phenyl-4- (3-pyridinyl) -2-pyrimidinamine 0.9 N-(4-Acetylphenyl)-4-(3-pyridinyl,-2pyrimidinamine 0.8 N—(4-Fluorophenyl)-4-(3-pyridinyl)-2pyrimidinamine <48 N-(4-Me thoxyphenyl )-4-(2-pyridinyl )-2-pyrimidinamine 8.3 N-( 4 -Me thoxyphenyl) -4- (4-pyridinyl) -2-pyrimidinamine 1.0 N- (4-Fluorophenyl, -4-( 4-pyridinyl) -2-pyrimidinamine 1.9 N—( 4—Bromophenyl )-4-( 3-pyridinyl) -2-pyrimidinamine 2.3 4- (3-Pyridinyl) -N- (3-( trifluoromethyl) phenyl ] 2-pyrimidinamine, hydrochloride 0.7 4-( 2-Pyridinyl) -N-( 3-( trif 1 uoromethyl) phenyl ] 2-pyrimidinamine" 2.9 N-(4-Methoxyphenyl)-4-(2-thienyl)-2-pyrimidinamine 3.9 -11TABLE I (continued) Compoundic50(um) N- (4-Ethylphenyl) -4- (1-methyl-lH-pyrrol -2y1)-2-pyrimidinamine <48 N-Phenyl-4-(2-thieny1) -2-pyrimidinamine 31.7 N-(3-Chloro-4-methylphenyl ,-4-(3-pyridinyl,-2pyrimidinamine 9.3 N—( 3—Methylphenyl )-4-( 2-pyridinyl) -2-pyrimidinamine 0.7 N—( 3-Methylphenyl) -4-(4-pyridiny1) -2-pyrimidinamine 9.4 N-Phenyl-4-( 4-pyridinyl) -2-pyrimidinamine 0.9 N- (3-Methylphenyl )-4-( 3-pyridinyl) -2-pyrimidinamine 1.5 N— (4-Ethylphenyl ,-4-( 4-pyridinyl) -2-pyrimidinamine 7.7 N-( 4-Ethylphenyl )-5-methyl-4-( 4-pyridinyl )-2pyrimidinamine <48 N-(4-Ethylphenyl ,-4-(3-pyridinyl,-2-pyrimidinamine <48 N- (4-Ethylphenyl ,-4-( 2-pyridinyl, -2-pyrimidinamine 2.1 N- (3-Methylphenyl ,-4-( 2-thieny 1) -2-pyrimidinamine 0.3 4-( 2-Furanyl, -N-phenyl-2-pyrimidinamine 48 4-(2 -Furany 1, -N- (3 -me thy lpheny 1,-2 -pyrimi dinamine 3.5 N- (4-Ethylphenyl ,-4-( 6-methy1-3-pyridiny1, -2pyrimidinamine 13.4 -12TABLE I (continued) Compound IC5q(μΜ) N—(4—Ethylphenyl)-6-methyl-4-(6-methyl-3pyridinyl)-2-pyrimidinamine 19.1 N—(4-(4—Methyl—1—piperazinylJphenyl1—4—(2— thienyl)-2-pyrimidinamine <24 N-(4-Ethylphenyl)-4-pyrazinyl-2-pyrimidinamine 2.8 N-(3-MethyIpheny1)-4-pyrazinyl-2-pyrimidinamine 5.4 N-(2-Methylphenyl)-4-(4-pyridinyl)-2-pyrimidinamine 3.9 N—(3-EthyIpheny1)-4-(4-pyridinyl)-2-pyrimidinamine 10.6 N-(2,5-Dimethylphenyl)-4-(4-pyridinyl)-2pyrimidinamine 47.1 N-(2,3-Dimethylphenyl)-4-(4-pyridinyl)-2pyrimidinamine 20.2 N-(3-Methylpheny1)-4-(3-thienyl)-2-pyrimidinamine 3.8 N-(2,5-Dimethylphenyl)-4-(2-pyridinyl)-2pyrimidinamine <48 N— (3,5-Dimethylphenyl)-4-(4-pyridinyl)-2pyrimidinamine 4.4 N-l-Naphthaleny1-4-(4-pyridinyl)-2-pyrimidinamine 31.3 N-(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2pyrimidinamine 1.0 N-l-Naphthalenyl-4-(2-pyridinyl-2-pyrimidin- amine 3.0 N-(2,4-DimethyIpheny1)-4-(4-pyridinyl)-2pyrimidinamine 24.0 -13TABLE I (continued) Compound IC5(j(yM) 4—(4—Pyridinyl)-N-(2,4,6-trimethyIpheny1)-2pyrimidinamine 10.5 4-(2-Furanyl) -N-(4-methoxyphenyl) -2-pyrimidinamine <48 N-[4-(4-Methyl-l-piperazinyl)phenyl]-4-(2pyridinyl)-2-pyrimidinamine <24 4-( 2-Furanyl) -N- (3-( trifluoromethyl) phenyl 1-2pyrimidinamine <48 N-( 4-Fluorophenyl) -4- (2-f uranyl) -2-pyrimidinamine 13.3 N-Cyclopentyl-4-( 2-pyridinyl )-2-pyrimidinamine 2.2 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, compound with 2-hydroxy-1,2,3-propanetricarboxy late (2:1) 2.5 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, (Z)-2-butenedioate (1:1) 1.0 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, sulfate 3.0 N-Phenyl-4-(4-pyridinyl,-2-pyrimidinamine, dinitrate 1.2 N-(4-EthyIpheny1)-4-(4-pyridinyl)-2-pyrimidinamine, pyridine-l-oxide 17.7 N— (3,4-DimethyIpheny1)-4-(2-pyridinyl)-2pyrimidinamine 5.9 N-(4-Methoxyphenyl)-4-(3-thienyl)-2-pyrimidinamine 15.6 N-(3-EthyIpheny1)-4-(2-furanyl)-2-pyrimidinamine 9.7 4-(lH-Indol-3-yl)-N-phenyl-2-pyrimidinamine 3.0 -14TABLE I (continued) j Compound 1 N-(2-Methoxy-5-methylphenyl)-4-(4-pyridinyl )2-pyrimidinamine 6.9 N-(3-Methylphenyl)-4-(1-methy1-ΙΗ-pyrro1-2yl)-2-pyrimidinamine 9.4 N- (3-Ethylphenyl )-4-( 2-thieny1) -2-pyrimidinamine 48.0 N-(3-Ethy lphenyl ,-4-(3-thienyl)-2-pyr imidinamine 1.1 4—(1H—Indol—2—yl )-N-( 3-me thy lphenyl) -2-pyr imidinamine 2.2 4-((4-(4-Pyridinyl)-2-pyrimidiny11amino]benzoic acid, methyl ester 27.5 N— (3-Me thy lphenyl) -4-(4-quinolinyl) -2-pyr imidinamine 10.9 N-Phenyl-4-(-4-quinolinyl) -2-pyrimidinamine 3.0 N-(4-Ethylphenyl)-4-(4-quinolinyl)-2-pyrimi dinamine 4.0 4-( 2-Pyridinyl) -N- (3-( trif luoromethyl) phenyl ] 2-pyrimidinamine, sulfate 3.0 N- (3-Me thy lphenyl) -4- (2-thieny 1) -2-pyrimidinac-ine, sulfate 3.0 4-(2-Puranyl )-N-(3-(methylphenyl) ]-2-pyrimidinamine, sulfate 3.0 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, phosphate 3.3 N- (3,5-Dimethylphenyl ,-4-( 2-f urany 1) -2-pyrimi dinamine 0.7 N-(3,5-Dimethylphenyl,-4-(2-thieny 1,-2-pyrimidinamine 4.3 -15TABLE I (continued) Compound 1 IC50 (MM) N-(2,4-Difluorophenyl)-4-(4-pridinyl)-2pyrimidinamine <48 N-(2,4-Difluorophenyl)-4-(3-pyridinyl)-2pyrimidinamine <48 N-(3-Methylphenyl)-4-(5-methyl-2-thienyl)2-pyrimidinamine 1.4 N-(2,6-Difluorophenyl)-4-(4-pyridinyl)-2pyrimidinamine 2.9 4-(4-Pyridinyl)-N-[3-(trifluoromethyl)phenyl]2-pyrimidinamine, sulfate <48 N-(4-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine, sulfate <48 N-Pheny1-4-(3-pyridinyl)-2-pyrimidinamine, sulfate 3.0 4-(3-Pyridinyl)-N-(3-( trifluoromethyl)phenyl]2-pyrimidinamine, sulfate 2.6 N-Pheny1-4-(4-pyridinyl)-2-pyrimidinamine, dihydrochloride 3.0 N-(4-(1,1-Dimethylethyl)phenyl]-4-(3-pyridinyl)-2-pyrimidinamine 0.7 N-(2,6-Difluorophenyl)-4-(3-pyridinyl )-2pyrimidinamine 22.0 N-(4-Ethylphenyl)-4-(5-methyl-2-thienyl)-2pyrimidinamine 36.3 N-[ (3,4-Dimethylphenyl)methyl]-4-(2-pyridinyl2-pyrimidinaraine 39.8 N-(3,5-Dimethylpheny1)-4-(3-pyridinyl)-2pyrimidinamine, sulfate 3.0 N-(3,5-Dimethylpheny1)-4-(3-pyridinyl)-2pyrimidinamine, phosphate 3.0 -16TABLE I (continued) Compound 1 IC5Q(yM) N-(3-Methylphenyl)-4-(lH-pyrrol-2-yl)-2pyrimidinamine 11.1 4-(5-Methyl-2-furanyl)-N-(3-methylphenyl)-2pyrimidinamine 2.0 4-Methyl-6-(5-methyl-2-thienyl)-N-phenyl-2pyrimidinamine 24.8 N-[4-(Dimethylamino)phenyl]-4-(4-pyridinyl)-2pyrimidinamine 3.8 N-(3-Methoxyphenyl )-4-(4-pyridinyl)-2-pyrimidinamine 0.4 N-(3-Methoxyphenyl)-4-(2-pyridinyl)-2-pyrimidinamine 0.2 N-[4-(Dimethylamino)phenyl1-4-(2-pyridinyl)-2pyrimidinamine 2.7 N-(3-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine 0.3 N-(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2pyrimidinamine 0.8 4-([4-(3-Pyridinyl)-2-pyrimidinylJamino]benzoic acid, ethyl ester 12.4 N,N-Dimethyl-N·-(4-(3-pyridinyl )-2-pyrinlidinyll-l,4-benzenediamine 3.7 4-(2,5-Dimethyl-3-furanyl)-N-phenyl-2-pyrimidinamine 2.0 N,N-Dimethyl-N·-(4-(4-pyridinyl)-2-pyrimidi nyl )benzenediamine, trihydrochloride 0.4 4-(2,5-Dimethy1-3-furanyl)-N-(3-methylphenyl)2-pyrimidinamine 28.5 4-(2,5-Dimethy1-3-furanyl)-N-(3,5-dimethylpheny1-2-pyrimidinamine 4.1 -17TABLE I (continued) Compound 1 IC50(pM, N,N-Dimethyl-N’-{4-(2-pyridinyl)-2-pyrimidinylj-l,4-benzenediamine, dihydrochloride 4.4 4-(2,5-Dimethy1-3-furany1,-N-(4-ethylphenyl)-2-pyrimidinamine 19.2 N,N-Dimethyl-N·-(4-(3-pyridinyl)-2-pyrimidiny1]-1,3-benzenediamine 1.7 3-1(4-(2-Pyridinyl)-2-pyrimidiny1]amino]benzoic acid, ethyl ester 3.0 N, N-Dimethyl-N' — [ 4—(2-pyridinyl) -2-pyrimidinyll-l,3-benzenediamine 0.5 4-((4-( 3-Pyridiny1) -2-pyr imidiny 1 ] amino ] phenol 5.1 3-((4-(3-Pyridiny1)-2-pyrimidiny1]amino]benzoic acid, ethyl ester 20.3 N—(4-Methoxypheny1)-4-(3-pyridinyl,-2-pyrimi dinamine, phosphate 3.2 N— (3,5-Dimethylphenyl,-4-(2-pyridinyl,-2pyrimidinamine, sulfate 0.6 N—[4—(2-Propenyloxy,phenyl]-4-(3-pyridinyl,-2pyrimidinamine 0.8 N-(4-(2-(Dimethylamino,ethoxy]phenyl]-4(3-pyridinyl,-2-pyrimidinamine 0.5 N-Pheny1-4-(3-pyridiny1,-2-pyrimidinamine, phosphate 2.7 Ν'-14-(2-Furanyl)-2-pyrimidiny11-N,Ndimethyl-1,4-benzenediamine 1.9 N,N-Dimethyl-N'-(4-(2-thienyl)-2-pyrimidinyl]1,4-benzendiamine 0.6 N'-(4-(2,5-Dimethyl-3-furanyl,-2-pyrimidiny1]Ν,Ν-dimethyl-1,4-benzenediamine 4.9 -18TABLE I (continued) Compound IC50(pM) N,N-Dimethyl-N’-i4-(3-methyl-2-thienyl )-2pyrimidinyl]-I,4-benzenediamine N-(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2pyrimidinamine, phosphate N,N-Dimethyl-N’-(4-(3-pyridinyl)-2-pyrimidinylj-l,4-benzenediamine, trihydrochloride N,N—Dimethyl—N’-(4-(4-pyridinyl )-2-pyrimidiny lj-l,3-benzenediamine N,N-Dimethy1-N·-(4-methy1-6-(4-pyridiny1)-2pyrimidinyl]-1,4-benzenediamine N—(4—(3-Dimethylamino)propoxy]phenyl)-4-(3pyridinyl)-2-pyrimidinamine N-(4—(2-Diethylamino)ethoxy]phenyl)-4-(3pyridinyl)-2-pyrimidinamine N—[4—[2-Dimethylamino)ethoxy]phenyl)-4-(3pyridinyl) -2-pyrimidinamine, hydrochloride 4-((4-( 3-Pyridinyl) -2-pyrimidiny 1) amino ] benzoic acid N, N-Dimethyl-N *—(4— (2-pyridinyl) -2-pyrimidinyll-l, 3-benzenediamine, dihydrochloride N, N-Dimethyl-N · - (4-( 2-pyridinyl) -2-pyrimidinylT-1,3-benzenediamine, trihydrochloride N—(3,5-Dimethylphenyl)-4-(2-furanyl)-5-methyl2-pyrimidinamine N, N-Dimethyl-N' -(4-( 4-pyridinyl)-2-pyrimidinylj-1,3-benzenediamine, dihydrochloride N’-(4-(2-Furanyl )-5-methyl-2-pyrimidinyl ]-N,Ndimethyl-1,4-benzenediamine I 1.8 0.3 1.5 3.5 37.7 0.5 0.2 0.5 7.6 0.5 1.0 <24 0.5 6.1 -19TABLE I (continued) Compound 1 IC50(yM) 4-( 2-Furanyl )-5-methyl-N-phenyl-2-pyrimidinamine, sulfate 5.0 N* -14-(2-Benzof urany 1) -2-pyrimidiny 1 ] -N, N-dimethyl-1,4-benzenediamine 5.6 4-Methyl-N-pheny1-6-(2-pyridinyl) -2-pyrimidinamine 26.8 4-((4-(4-( Pyridinyl) -2-pyrimidiny 11 amino ] phenol 3.3 N-l 4-(2-(Dime thy lamino)ethoxy ]pheny 1 ]-4-( 4pyridinyl)-2-pyrimidinamine 1.5 N-14-12- (Dimethylamino) ethoxy ] phenyl ]N’,N'dimethyl-N-f 4-( 4-pyridinyl) -2-pyrimidiny 1 ] 1,2-ethanediamine 9.1 N-( 4-( 3-D ime thylamino) propoxy Ipheny 1 ]-4-(4pyridinyl)-2-pyrimidinamine 1.3 N-14-(2-(Diethylamino) ethoxy ] phenyl ] -4 - (4 pyridinyl) -2-pyrimidinamine 0.2 4-(2-(( 4-Methoxyphenyl )amino J -4-pyrimidinyl ] 1-methylpyridinium, iodide 33.3 N,N-Dimethyl-N*-(4- (4-pyridinyl) -2-pyrimidinyl)]-l,3-benzenediamine, sulfate 1.0 N,N-Dimethy1-N · - (4- (2-thieny 1) -2-pyrimidiny 1 ] 1,3-benzenediamine 2.4 N, N-Dimethy 1-N*-(4-( 5-methy 1-2-furanyl) -2pyrimidinyl ] -1,3-benzenediamine 1.6 N* -[4—(2,5-Dimethyl-3-f urany 1 )-2-pyrimidinyl ] N,N—dimethyl—1,3-benzenediamine <24 N-(2-(Diethylamino)ethyl]-4-((4-(3-pyridinyl)-2-pyrimidinyl1amino]benzamide 0.8 -20TABLE I (continued) Compound 1 IC5Q(yM) 4-1(4-(4-Pyridinyl)-2-pyrimidiny1]amino]phenoxy]acetic acid, ethyl ester 5.8 N,N—Diethyl-Ν'—(4-(4-pyridinyl)-2-pyrimidinylT-l,4-benzenediamine 1.1 N,N-Dimethy1-N’-(4-methy1-6-(2-pyridiny1)-2pyrimidiny1]-1,4-benzenediamine 31.8 N—I4-(lH-Imidazol-l-yl)phenyl]-4-(4-pyridinyl) -2-pyrimidinamine 12.3 N—(4—{4—Pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine, hydrochloride 3.0 N,N-Diethyl-N'-(4-(3-pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine 1.7 N—(4-(lH-Imidazol-l-yl)phenyl)-4-(3-pyridinyl ) -2-pyrimidinamine 1.3 1-(4-((4-(3-Pyridiny1)-2-pyrimidiny1]amino ] phenyl]ethanone, oxime 11.4 1-(4-((4-(3-Pyridinyl)-2-pyrimidiny1]amino ] phenyl]ethanone, O-methy1oxime 5.1 N, N-Diethyl-N' -(4-( 2-pyridinyl) -2-pyrimidinylT-1,4-benzenediamine 10.1 N—14—(IH—Imidazol—1—yl )phenyl ] -4-( 2-pyri'dinyl)-2-pyrimidinamine 1.8 4-(2-Furanyl)-N-(4-(lH-imidazol-l-y1)phenyl]2-pyrimidinamine 2.2 N-Methyl-4-((4-(3-pyridinyl)-2-pyrimidiny1]amino]-benzamide 4.6 N,N-Dimethyl-Ν'-(4-(5-methy1-2-thienyl )-2pyrimidiny1]-1,3-benzenediamine 5.7 -21TABLE I (continued) Compound 1 ICsq(pM) N,N-Dimethyl-N'-(4-(3-thienyl)-2-pyrimidinyl]1,4-benzenediamine 2.1 N-(1-(4-((4-(3-Pyridiny1,-2-pyrimidinyl]amino]phenyl]ethyl]formamide 0.4 N~l4-(1-Aminoethyl)phenyl]-4-(3-pyridiny1)2-pyrimidinamine, trihydrochloride 0.8 4-((4-(3-Pyridiny1)-2-pyrimidiny1]aminoJbenzenesulfonamide 0.2 N—(3-Chlorophenyl,-4-(4-pyridinyl)-2-pyr imidinamine 3-1 N-(3-Chlorophenyl)-4-(3-pyridinyl)-2-pyrimidinamine 1.5 N—(3-Methoxyphenyl)-4-(3-thienyl)-2-pyrimidinamine 1.7 N-Methyl-N-(4-((4-(3-pyridinyl)-2-pyrimidinyl ] amino ] phenyl ] acetamide 1.1 N-Methyl-N-(4-((4-(4-pyridinyl,-2-pyrimidiny1]amino]phenyl]acetamide 0.1 N-Methyl-N-f 4-((4-(2-pyridinyl,-2-pyrimidinyl]aminolphenyl]acetamide 0.6 (4-( 2-Furanyl) -M- (3-methoxyphenyl) -2-pyrimidinamine 0.3 4-(2-Benzofurany1)-N-(3-methoxyphenyl)-2pyrimidinamine 1.2 Oxo(phenyl(4-(4-pyridinyl,-2-pyrimidinyl]amino]acetic acid, ethyl ester 2.1 N-f4—((4-(4-Pyridinyl,-2-pyrimidinylJamino]phenyl]acetamide 5.3 -22TABLE I (continued) Compound IC50(uM) N,N-Dimethyl-N’-(4-(2-furanyl)-5-mcthyl-2pyrimidinyl J-l, 3-benzenediamine 40 N-l4-((4-(3-Pyridinyl)-2-pyrimidinylJaminoJphenyl (acetamide 3.6 4-( (4-(2-Pyridinyl)-2-pyrimidinylJarainoJbenzenesulfonamide 4.5 N-(4-( (4-(2-Pyridinyl)-2-pyrimidinyl Jamino]pheny1]acetamide 1.5 N— (3-Methoxyphenyl)-4-(2-thi eny1)-2-py r i midinamine 0.9 N—( 4-( 4—Methyl—1—piperazinylJphenyl]-4-(3pyridinyl) -2-pyrimidinamine 1.5 N-(3-Methoxyphenyl,-4-(5-methyl-2-thienyl)2-pyrimidinamine 2.3 N—(3—Chlorophenyl)-4-(2-pyridiny1)-2-pyrimidinamine 1.3 4-(2-Furany 1) —N- (4- (4-me thy 1 -1-pi peraz i ny 1) phenyl ] -2-pyr imidi namine 1.8 fi-(4—(4-Methyl-l-piperazinyl)phenyl]-4-(4pyridinyl)-2-pyrimidinamine 0.6 (3-Methoxyphenyl)-4-(2,5-dimethyl-3-furanyl) -2-pyrimidinamine 5.8 H"(4-(2-Pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine, dihydrochloride 1.0 H-(3-Fluorophenyl)-4-(4-pyridinyl)-2-pyrimidinamine 0.7 U-(3-Fluorophenyl)-4-(3-pyridinyl)-2-pyrimidinamine 3.3 H-(3-Fluorophenyl)-4-(2-pyridinyl)-2-pyrimidinamine 0.9 1-(3-((4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyljethanone 4.1 -23TABLE I (continued) Compound IC5O N-Methyl-N'-(4-(3-pyridinyl)-2-pyrimidiny1]1,4-benzenediamine 2.1 fi- (4-(1-Methylethyl) phenyl]-4-(3-pyridiny1) 2-pyrImidinamine 1.1 H-Methyl-N' -(4 - (2-pyridinyl) -2-pyrimidinyl ] 1,4-benzenediamine 1.4 E-(3-Ethylphenyl) -4-(3-pyridinyl) -2-pyrimidinamine 1.7 H-(3-Ethylphenyl)-4-(2-pyridinyl)-2-pyrimidinamine 1.4 3-( (4-(2-Pyridinyl)-2-pyrimidinyl]amino] benzenesul f onamide 0.7 3-( (4-(3-Pyridinyl) -2-pyrimidinyl]amino]benzenesulfonamide 0.2 [4—(1,1—Dimethylethyl)phenyl]-4-(2-thienyl) 2-pyrimidinamine 4.6 H/N-Diethyl-N'-(4-(2-furanyl)-2-pyrimidinyl]1,4-benzenediamine 3.4 3-((4-(4-Pyridinyl,-2-pyrimidinyl]amino]benzenesulfonamide 0.5 N-Dimethyl-N·-(4-(4-pyridinyl)-2-pyrimidinyl ]-1,2-benzenediamine, fumarate 36.2 2-(1-(4-([4—(3—Pyridinyl)-2-pyrimidinyl]amino] phenyl]ethylidene]hydra2inecarboxamide 8.1 N-(4-(2-(bis (1,1-Dimethylethyl) amino]ethoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine 4.6 a—Methyl-4—[(4-(3-pyridinyl)-2-pyrimidinyl]amino]benzenemethanol 4.5 N-[1-(3-((4-(3-Pyridiny1)-2-pyrimidinyl]amino]phenyl]ethyl]formamide 4.6 N—[3—((4-(4-Pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide 2.1 -24TABLE I (continued) Compound IC5O(^) N-(3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide 5.0 N- [ 4-(3-Pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine, dihydrochloride 0.4 N,N-Diethyl-Ν'-(4-(5-methy1-2-furany1)-2pyrimidinyl]1,4-benzenediamine 28.0 N-(3-Methoxyphenyl)-4-(5-methyl-2-furanyl)-2pyrimidinamine 1.2 N-[3-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide 0.3 N-[3-(lH-Imidazol-l-yl) phenyl]-4-(2-pyridinyl)-2-pyrimidinamine 0.1 N-(4-(4-Pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine 1.0 N—[2-Methyl-4-([4-(4-pyridinyl)-2-pyrimidinyl] amino] phenyl] acetamide 1 i 1.2 2-Methyl-N-(4-(4-pyridinyl)-2-pyrimidinyl]- j 1,4-benzenediamine, dihydrochloride i 0.9 ϋ-[4-(2-Pyridinyl) -2-pyrimidinyl ] -l, 3-benzenediamine 0.2 H- [4-((4-( 5-Methyl-2-thienyl) -2-pyrimidinyl ] amino]phenyl]acetamide 0.3 H- [ 3 - (1-Aminoethyl) phenyl ] -4- (3-pyridinyl) -2pyrimidinamine, trihydrochloride 5.1 H- [3-[ 2- (Diethylamino) ethoxy]phenyl ] -4-(3pyridinyl)-2-pyrimidinamine 2.8 E~ (2-Methoxyphenyl) -4- (3-pyridinyl) -2-pyrimidinamine 9.8 N—[4—[ [4-(2-Thienyl)-2-pyrimidinyl]amino]phenyl]acetamide 0.2 N- [ 2-Methyl-4-(4 - (3-pyridinyl) -2-pyrimidinyl ] phenyl]acetamide 1.8 H ‘ [ 4 - (2 -Benzo f uranyl) -2 -pyrimidiny1 ] -N, Ndiethyl-1,4-benzenediamine 6.2 -25TABLE I (continued) Compound ICSO^) N-(4-([4-(2-Furanyl)-2-pyrimidinyl]amino]phenyl]acetamide 0.7 N-[4-(ΙΗ-Imidazol-l-yl)-3-(trifluoromethyl)phenyl]-4-(4-pyridinyl)-2-pyrimidinamine 0.4 N—[3 — (ΙΗ-Imidazol-l-yl) phenyl)-4-(3-pyridinyl) -2-pyrimidinamine 0.1 2-( [4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol 23.5 4-(2-Furanyl)-N-(3-(lH-imidazol-l-yl) phenyl]2-pyrimidinamine 0.8 N-[3-[2-(Diethylamino) ethoxy]phenyl)-4-(2furanyl)-2-pyrimidinamine 1.3 N-[4-(ΙΗ-Imidazol-l-yl)-3-(trifluoromethyl) phenyl]-4-(2-pyridinyl)-2-pyrimidinamine 1.6 N-[3-[2-(Diethylamino)ethoxy]phenyl)-4-(2thienyl)-2-pyrinidinamine 0.6 J ί 1 JJ— (3- [ 2- (Diethy lamino) ethoxy] phenyl ] -4- (4pyridinyl) -2-pyrimidinamine 0.7 H-[4-( 4-Pyridinyl)-2-pyr imidiny 1)-1,4-benzenediamine 2.4 N-[3-(IH-Imidazol-1-yl)phenyl]-4-(4-pyridinyl) 2-pyrimidinamine O.H- N-[3-(1H-Imidazol-1-yl)phenyl)-4-(2-thienyl)-2pyrimidinamine O.X The ability of these compounds.to inhibit lipoxygenase activity in terms of the suppression of the release and biosynthesis of leukotriene B4(LTB4) and -hydroxy-eicosatetraenoic acid (5-HETE) was measured as follows.
In this assay 3x10? peritoneal neutrophils derived from guinea pigs were incubated at 37°C in -26Dulbeccos buffer containing 50mM tris buffer (pH 7.4)Five minutes before the addition..of 100 μΜ arachidonic acid and 20 μΜ calcium ionophore (A23187), control vehicle or the test compounds were added to the neutrophils at a concentration of 10 ug/ml· Three minutes after the addition o£ arachidonic acid and calcium ionophore the total lipid was partitioned into chloroform after adjusting the pH to 3 with citric acid and the addition of equal parts of methanol and chloroform.
The 5-HETE and LTB4 were resolved by HPLC using a 5 yM 4x25 cm octadecyl silica column (IBM Instruments) with 70-80% methanol in water adjusted to pH 3.0 with acetic acid. As the mobile phase was pumped at 1.0 ml/minute, LTB4 and 5-HETE were detected by absorbance at 270 and 236 nm, respectively.
LTB4 and 5-HETE were quantitated by comparison with the control and the results were expressed as a percent of control. The lower the percentage, the more active the compound.
The results of this test on representative compounds of this invention appear in Table II. -27TABLE II Inhibition of Neutrophil Lipoxygenase from Immunologlcally Stimulated Guinea Pig Neutrophlles Compound % Inhibition LTB4 5-HETE 4-(3-Pyridinyl)-N-(3-trifluoromethyl)phenyl}-2-pyrimiZinamine N-(4-Acetylphenyl)-4-(3-pyridinyl,-2pyrimidinamine 56.1 37.0 N-(4-Fluorophenyl)-4-(2-pyridinyl,-2pyrimidinamine 45.0 N-(4-Methylphenyl,-4-(4-pyridinyl)-2pyrimidinamine 45.0 N-(4—Fluorophenyl)-4-(4-pyridinyl,-2pyrimidinamine 53.0 4-(3-Pyridinyl,-N-ί 3-trifluoromethyl)phenyl,-2-pyrimiSinamine S8.0 N-Pheny 1-4-( 4-pyridiny 1,-2-pyrimidinamine 58.0 N-(3-Wethylphenyl,-4-(3-pyridinyl ,-2pyrimidinamine 40.0 N-(4-Ethylpheny1)-4-(4-pyrid i ny1)-2pyrimidinamine 33.9 41.0 N-(4-Ethylphenyl,-4-(2-pyridinyl)-2pyrimidinamine 29.5 41.0 4-<2-Furanyl,-N-(3-methylphenyl)-2-pyrimidinamine 7.4 3.0 N-ί 4-(4-Methy1-1-piperarinyl, phenyl 1-4(2-thienyl)-2-pyrimidinamine 48.0 -28TABLE II (continued) Compound % Inhibition LTB4 5-HETE N- ( 4 -Ethy lpheny 1 )-4-(6 -methyl -3 -py r id inyl)-2-pyrimidinamine 53.4 54.0 N- (3 -Methylpheny1) -4 -pyrazi ny 1 -2 -pyr imi dinamine 50.0 N- (3-Ethy lpheny 1 )-4-(4 -pyridinyl )-2pyrimidinaaine 36.4 28.7 N-(2,3-Dimethylphenyl )-4-(4-pyridinyl )-2pyrimidinamine 58.4 N-Pheny1 -4-(3 - thieny 1)-2 -py r imidi nami ne 56.0 N-(3-Methylphenyl )-4-( 3-thienyl)-2-pyrimidinamine 48.0 N- (4 -Ethylpheny 1) -4 - (3-thieny 1) -2 -pyr imi dinamine 56.0 N-(2,4-Dimethylphenyl )-4-(2-pyridinyl )-2pyrimidinamine 54.0 N-( 3,5-Dimethylphenyl) -4-(4 -pyridinyl )-2pyrimidinaaine 53.1 54.0 N-(2-Methoxyphenyl )-4-(4-pyridinyl )-2pyrimidinaaine 17.4 21.0 N-( 2,5 -Dime thoxyphenyl )-4-(4-pyridinyl )2 -pyrimidinamine 43.2 47.0 N-(2,4-Dimethylphenyl )-4-( 4-pyridinyl )-2pyrimidinamine 37.0 43.0 N- (2-Methoxy-5-methylpheny1 )-4-( 2-pyridinyl )-2-pyrimidinamine 54.0 -29TABLE II (continued) Compound % Inhibition LTB4 5-HETE 4-(4-Pyridi ny1)-N-(2,4,6-trimethy1phenyl)2-pyrimidinamine 53.6 4-(2-Furany1)—N—(4-methoxyphenyl)-2pyrimidinamine 44.0 4—< 2-Furany1)-N-l3-trifluoromethyl)phenyl]-2-pyrimidinamine 45.0 49.0 N-{4-Fluorophenyl)-4-(2-furany1)-2-pyrimidinamine 33.0 N-Phenyl-4-( 4-pyridinyl)-2-pyrimidinamine, compound with 2-hydroxy-1,2,3-propanetricarhoxylate (2:1) 58.0 N-l(3,4-Dimethylphenylimethyl]-4-(4pyridinyl)-2-pyrimidinamine 24.0 36.0 N-Phenyl-4-( 4-pyridinyl)-2-pyrimidinamine, sulfate S6.0 4-(2-Benzofurany1)-N-(3-toe thy Ipheny 1 )-2pyrimidinamine 46.1 N-(4-Ethylphenyl)-4-(4-pyridinyl)-2pyrimidinamine 19.0 N-(3,4-DimethyIpheny1)-4-(4-pyridinyl)-2pyrimidinamine 19.0 N-(3,4-DimethyIpheny1)-4-(2-pyridinyl)-2pyrimidinamine 17.3 35.0 N-(4-Fluorophenyl,-4-(3-thienyl)-2-pyrimidinamine 51.6 4-(10H-Phenothiazin-2-yl)-N-pheny1-2pyrimidinamine 48.0 -30TABLE II (continued) Compound % Inhibition LTB4 5-HETE 4-( ΙΗ-Indol-3 -y 1) -N-pheny 1 -2-pyr imidi namine 41.2 39.0 N- (2-Methoxy-5-methylpheny1) -4- (4-pyridinyl )-2-pyr imidinamine 44.7 37.0 N-(3-Methylphenyl )-4-( 1-methyl-lH-pyrrol2-yl)-2-pyrimidinamine 60.0 4-( l-Methyl-lH-pyrrol-2-yl) -N-phenyl-2pyrimidinamine 57.0 N— (4-Ethylphenyl )-4-( lH-indol-3-yl) -2pyrimidinamine 56.5 N—11,1 * -Biphenyl J-4-y 1-(4 -pyridinyl )-2pyr imidinamine 37.1 45.0 4-( (4-(4-Pyridiny1)-2-pyrimidiny 1 ]-amino]benzoic acid, methyl ester 45.2 47.0 N— (.3-Methylphenyl )-4-( 4-quinol inyl )-2pyrimidinamine 16.0 N-Pheny 1-4-( 4-quinol iny 1)-2-pyrimidinamine 46.4 57.0 N-(4-Ethylphenyl)-4-(4-quinolinyl )-2pyrimidinamine 58.0 N-(3,5-Dime thylpheny 1 )-4-(2-f uranyl )-2pyrimidinamine 56.1 N-( 4-(1,1-Dimethylethyl)phenyl J-4-(4pyridinyl)-2-pyrimidinamine 47.8 54.0 N-MethyI-N-pheny1-4-(2-pyridinyl)-2pyrimidinamine 58.1 54.0 -31TABLE II (continued) 1 Compound % Inhibition LTB4 5-HETE N-Pheny 1-4-( 1H-pyrro 1 -2 -y 1) -2-pyrimi dinamine 55.4 N—(4—Ethylphenyl )-4-(lH-pyrrol-2-yl )-2pyrimidinamine 32.6 54.0 4-(3-Pyridinyl)-N-(3-(trifluoromethyl)phenyl ]-2-pyrimidinamine sulfate 37.3 49.0 N-Pheny1-4-(4-pyridinyl) -2-pyrimidinamine, dihydrochloride 48.0 43.0 4- (3-Methyl-2-thienyl) -N-phenyl-2-pyrimi|dinamine ~ 59.0 4-( 5-Methyl-2-f uranyl) -N-( 3-methyl phenyl) 2-pyrimidinamine ~ 59.6 4-Me thy 1-6-( 5-me thy 1-2-thi enyl) -N-phenyl2-pyrimidinamine 42.3 52.0 N—[4—(Dimethylamino) phenyl J -4- (4-pyridinyl)-2-pyrimidinamine 16.6 12.4 N-(3-Methoxyphenyl,-4-(4-pyridinyl)-2pyrimidinamine 31.2 50.0 N"i 4—(Dime thy lamino,phenyl J-4-(2-pyridin— yl)-2-pyrimidinamine 20.1 17.2 N- (3,5-Dimethylpheny 1 )-4-(3 -pyr idiny 1) - 50.7 56.0 2-pyrimidinamine 4-((4-(3-Pyridinyl,-2-pyrimidinyl]amino]benzoic acid, ethyl ester 35.8 47.0 N,N-Dimethyl-N-*(4-(3-pyridinyl)-2-pyrimidiny1]-1,4-benzenediamine 43.4 34.0 -32TABLE II (continued) Compound % Inhibition LTB4 5-HETE 4-(2,5-Dimethyl-3-furanyl)-N-phenyl-2pyrimidinamine 46.9 56.0 N,N—Dimethyl—N*-(4-(4-pyridinyl)-2pyrimidiny1]—1,4—benzenediamine, trihydrochloride 40.7 37.0 N,N-Dimethyl-N’-(4-(2-pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine, dihydrochloride 37.6 39.0 4-([4—(3—Pyridinyl)-2-pyrimidinyl]amino]phenol 30.0 3-((4-(3-Pyridinyl)-2-pyrimidinyl]aminoJbenzoic acid, ethyl ester 36.1 50.0 N-(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2pyrimidinamine, sulfate 50.0 N-[4-(2-Propenyloxy)phenyl J-4-(3-pyridinyl)-2-pyrimidinamine 34.1 N' (4-(2-Furanyl) -2-pyrimidinyl ] -N,N-d imethy 1-1,4-benzenediamine 16.9 16.9 N,N-Dimethyl-N’-(4-(2-thienyl)-2-pyrimidinyl]-1,4-benzenediamine 49.8 17.8 N’-(4-(2,5-Diraethyl-3-furanyl)-2-pyrimidiny 1]-N,N-dimethy1-1,4-benzenediamine 21.6 17.0 N,N-Dimethyl-N’-(4-(3-methy1-2-thienyl)2-pyrimidinyl7-l,4-benzenediamine 16.4 13.6 N,N-Dimethyl-N·-(4-(3-pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine, trihydrochloride 46.8 42.0 N,N-Dimethy-N’-(4-(4-pyridinyl)-2-pyrimidiny 1 ]-1,3-benzenediamine 51.1 -3310 TABLE II (continued) Compound % Inhibition LTB4 5-HETE N,N-Dimethyl-N*-(4-methyl-6-(4-pyridinylT-2-pyrimidTnyl]-l, 4-benzenediamine 1.6 10.0 N-(3,5-Dimethylphenyl)-4-methyl-6-(3pyridinyl)-2-pyrimidinamine 32.7 40.0 Ν' —[4-(2-Furanyl )-5-methyl-2-pyrimidinyl ]N,N-dimethyl-1,4-benzendiamine 3.6 4-( 2-Furanyl) -5-methy1 -N-pheny 1-2-pyr imi dinamine, sulfate 52.4 Ν'-(4-( 2-Benzof uranyl) -2-pyrimidinyl ]-N,Ndimethyl-1,4-benzenediamine " 22.9 30.0 4-Methy1-N-pheny1-6-(2-pyridinyl)-2pyrimidinamine 30.3 42.0 4-((4-(4-Pyridinyl,-2-pyrimidinyl]-amino]phenol • 36.0 N-(4-Methoxyphenyl)-N-methyl-4-(4-pyridiny1-2-pyrimidinamine 57.4 N,N-Dimethyl-N’-(4-(2-thienyl)-2-pyrimidinyl ]-1,3-benzenediamine 39.6 50.0 N,N-Dimethyl-N*-(4-(5-methyl-2-furanyl)-2pyrimidiny1]-Σ,3-benzenediamine 31.1 37.7 E-Methyl-N’ - (4-(2-pyridinyl)-2-pyr imidinyl]-1,4-benzenediamine 24.1 53.6 H-[1-[3-[[4-(3-Pyridinyl)-2-pyrimidiny1]amino]phenyl]ethyl]formamide 34.0 )1-(4-( [4—(5—Methyl—2—thienyl)-2-pyrimidinyl]amino]phenyl]acetamide 51.0 46.0 H'-[4-(2-Benzofuranyl)-2-pyrimidinyl]-N,Ndiethy1-1,4-benzenediamine 51.0 45.0 E-(4-(lH-Imidazol-l-yl)-3-(trifluoromethyl ) phenyl]-4-(4-pyridinyl)-2pyrimidinamine 20.0 16.0 ! -345 TABLE II (continued) Compound % Inhibition LTB4 5-HETE U-(4-(5-Methyl-2-thienyl)-2-pyrimidinyl]1,4-benzenediamine, dihydrochloride 47.0 28.0 fi-(3-(ΙΗ-Imidazol-l-yl) phenyl)-4-(3-pyridinyl) -2-pyrimidinamine 50.0 51.0 H-(3-(1H-Imidazolyl) phenyl)-4-(2-thienyl) 2-pyrimidinamine 50.0 39.0 [4-(2-Furanyl)-2-pyrimidinyl)-1,4-benzenediamine, dihydrochloride 54.0 H-[4-(ΙΗ-Imidazol-l-yl)-3-(trifluoromethyl) phenyl] -4- (2-pyridinyl) -2-pyrimidinamine 19.0 4-([4-(2-Furanyl)-2-pyrimidinyl]amino]benzenesulfonamide 47.0 -35The novel compounds of the present invention are effective as antiasthmatic agents in mammals when administered in amounts ranging from about 0.1 mg to about 100 mg/kg of body weight per day. A preferred dosage regimen for optimum results would be from about 0.1 mg to about 25 mg/kg of body weight per day, and such dosage units are employed that a total of from about 7 mg to about 1.8 g of the active compound for a subject of about 70 kg of body weight are adminstered in a 24 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that these active compounds may be adminstered in any convenient manner such as by the oral, aerosol, intravenous, intramuscular, or subcutaneous routes.
The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may. be compressed into tablets or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 200 mg of active compound. -36The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustainedrelease preparations and formulations.
Compositions according to the present invention having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.10% to 10.0% by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Especially satisfactory are glycerin, propylene glycol, and polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, normally liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500. Although various mixtures of the aforementioned non-volatile polyethylene glycols may be employed, it is preferred to use a mixture having an average molecular weight of from about 200 to about 400. -37In addition to the active compound, the parenteral solutions may also contain various preservatives which may be used to prevent bacterial and fungal contamination. The preservatives which may be used for these purposes are, for example, myristyl-gamma-picolinium chloride, benzalkonium chloride, phenethyl alcohol, pchlorophenyl-alpha-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter, it is also convenient to employ antioxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulf oxy late. Generally, from about 0.0S% to about 0.2% concentrations of antioxidant are employed.
These compounds may also be administered by inhalation using conventional Aerosol* formulations.
The invention will be described in greater detail in conjunction with the following specific examples.
Example 1 4-(3-Pyridinyl, -N-( 3- (trifluoromethyl, phenyl ] -2pyrimidinamine A 7.04 g amount of 3-dimethylamino-l-(3-pyridinyl)-2-propen-l-one (0. S. Patent 4,281,000) and 18.72 g of (3-(trifluoromethyl )phenyl]guanidine carbonate in 500 ml of n-propanol was heated at reflux temperature for 16 hours. The solvent was evaporated to' near dryness, then water was added and the precipitate which formed was collected by filtration, then recrystallized from hexane to give 5.55 g of the desired product, mp 170-171®c.
Example 2 N—(4—Methoxyphenyl ,-4-( 3-pyridinyl)-2-pyrimidinamine A mixture of 14.4 g of 3-dimethylamino-l-(3pyridinyl,-2-propen-l-one and 16.1 g of 4-methoxyphenyl guanidine carbonate in 200 ml of isopropanol was heated at reflux for 20 hours. The reaction mixture was cooled, the crude product was collected by filtration and washed with water. The material was recrystallized from isopropanol -38to give the desired product as light yellow crystals, mp 121-122°C.
Example 3 N-(4-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine A 14.4 g amount of 3-dimethylamino-1-(4-pyridinyl)-2-propen-l-one (U. S. Patent 4,281,000) and 16.1 g of 4-methoxyphenylguanidine carbonate in 200 ml of isopropanol was heated at reflux for 24 hours. The solvent was evaporated to 1/3 volume, then the mixture was cooled in an ice-bath to crystallize the crude product. The product was collected by filtration and washed with water, then with isopropanol. The material was recrystallized from isopropanol/ethylene glycol monomethyl ether to give 16.7 g of the desired product as yellow crystals, mp 174175°C.
Example 4 N- (4-Methoxyphenyl )-4-( 2-thieny 1) -2-pyrimidinamine A mixture of 10.9 g of 3-dimethylamino-1-(2thienyl)-2-propen-l-one (0. S. Patent 4,374,988) and 11.8 g of 4-methoxyphenylguanidine carbonate in 150 ml of isopropanol was heated at reflux for 48 hours. The solution was cooled, then filtered, giving 9.0 g of the desired product as yellow crystals, mp 158-160^0.
Example 5 4-([4-(4-Pyridinyl)-2-pyrimidinyl]amino1benzoic acid, methyl ester A solution of 10.0 g of 4-guanidinobenzoic acid, hydrochloride in 310 ml of methanol was mixed with 6.0 ml (9.68 g) of thionyl chloride at 0©c for 15 minutes, then stirred for one hour at room temperature and then heated at reflux for 16 hours. The solvent ws removed in vacuo and the solid was washed with ether and air dried to give 11.4 g of white crystals (A).
The above procedure was repeated using 20.0 g of 4-guanidinobenzoic acid, 11.9 ml (19.4 g). of thionyl chloride and 600 ml of methanol to give 22.6 g of white crystals (B). -39The products (A) and (B) were combined and recrystallized from absolute ethanol. The product was washed with cold absolute ethanol and air dried giving 26.2 g of p-guanidinobenzoic acid, methyl ester, hydrochloride as white crystals, mp 137-138.5°C (dec.).
A 9.15 g amount of the above compound was partially dissolved in 100 ml of methanol (stored over 4A molecular sieves) and 2.15 g of sodium methoxide was added. The mixture was stirred briefly, then 7.0 g of 3-dimethylamino-1-(4-pyridinyl)-2-propen-l-one was added and the mixture was heated under argon with stirring for 21.5 hours. The reaction mixture was cooled in an ice bath, then filtered and washed with cold methanol. The residue was dissolved in a mixture of dichloromethane and methanol and filtered to remove sodium chloride. The filtrate was concentrated on a steam bath until crystal formation. The mixture was allowed to stand at room temperature for 16 hours then was filtered. The precipitate was washed with ice cold methanol then dried and gave 5.8 g of the desired product, mp 194.5-196.5<Ό.
Example 6 3-Dimethylamino-1-(3-indolyl)-2-propen-l-one A mixture of 3.18 g of 3-acetylindole and 5.17 ml. (4.36 g) of tert-butoxybis(dimethvlamino)methane was heated on a steam bath for 4 hours. The cooled reaction mixture was triturated with n-hexanes and gave a semisolid. The solvent was removed in vacuo and the material was triturated with dichloromethane giving 3.08 g of the desired compound as a tan crystalline solid, mp 239-245<>c.
Example 7 3-Dimethylamino-l-(5-n>ethyl-2-thienyl)-2-propen-l-one A mixture of 56.08 g of 2-acetyl-5-methylthiophene and 250 ml of Ν,Ν-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16 hours. The mixture was cooled in an ice bath and filtered giving 66.82 g of the desired compound, mp 118-121OC. -40Example 8 3-(Dimethylamino)-l-(5-methyi-2-furanyl)-2-propen-l-one A mixture of 37.24 g of 2-acetyl-5-methylfuran and 150 ml of Ν,Ν-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16.5 hours. The solvent was removed in vacuo and the residue taken up in dichloromethane and passed through a short column of magnesium silicate. The filtrate was evaporated on a steam bath with the addition of n-hexanes to a volume of 100-150 ml. Cooling with scratching gave 28.31 g of the desired compound, mp 123-125°C.
Example 9 3-( Dimethylamino )-1-( lH-pyrrol-2-y 1) - (E, -2-propen-l -one A mixture of 39.6 g of 2-acetylpyrrole and 104 ml (87.7 g) of tert-butoxy bis(dimethylaminoJmethane was heated on a steam bath for 20 minutes. The reaction was allowed to subside, then heating was continued for 6 hours. The mixture solidified then was slurried in hexane with chilling. The crude product was collected, washed with hexane and dried. The solid was dissolved in chloroform containing 5% methanol and filtered through magnesium silicate. The eluent was evaporated in vacuo and the residue was · recrystal lized from dichloromethane/hexane containing a small amount of methanol. The solid was collected, washed with hexane then dried' in vacuo giving .1 g of the desired compound as yellow crystals, mp 192193°C (dec.).
The following 3-(dimethylamino)acrylophenone intermediate compounds listed in Table III were prepared in a similar manner to the procedures described in Examples 6-6 and by those described in U. S. Patents 4,281,000, 4,374,988 and in Case 29,240, Serial number 672,753, filed on November 19, 1984. -41TABLE III 3-(Dimethylamino)acrylophenone Intermediates Rd II I r3-c-ch2 T5 + (CH3)2-N-C(OCH3)2 O R< Rs II I I r3—c—c=c-n( ch3 ) 2 Ex. *3 r4 Rs MP°C 10 2-Furany1 H H 84-86 11 2-pyridinyl H B 127-130 12 2-furanyl ch3 B Oil 13 4-pyridinyl ch3 B 106-108 14 6-methyl-3pyridinyl H B 116-118 15 6-methyl-3- pyridinyl H cb3 119-120 16 2-pyrazinyl H B 132-133 17 3-thienyl H B 89-90 18 4-quinolinyl H B 19 3-methyl-2thienyl H B 45-49 20 1-methyl-lH- pyrrol-2-yl H H 94-95 21 5-methy1-2thienyl H ch3 123-126 22 2,5-dimethyl3-furanyl H H 91-95 23 2-pyridinyl H ch3 68-70 -42TABLE III (continued) Ex. *3 r4 Rs MP°C 24 2-thienyl H ch3 97-99 25 4-pyridinyl H ch3 88-89 26 3-pyridinyl H ch3 62-64 27 3-pyridinyl ch3 H 76-78 28 3-methyl-2- pyridinyl H H 97-98 29 2-benzo- furanyl H H 137.0-138.5 30 3-pyridinyl H H 97-99 31 2-pheno- thiazine H H Examples 32-251 4,5,6-Substituted-2-pyrimidinamines The following 4,5,6-substituted-2-pyridinamine final products listed in Table IV were obtained by reacting a 3-(dimethylamino)acrylophenone from Table III and an appropriately substituted phenylguanidine base, carbonate, sulfate, nitrate or hydrochloride salt in an inert solvent such as absolute ethanol, n-propanol, isopropanol, 2-methoxyethanol, or n-butanol and the like, with or without a base such as sodium hydroxide, potassium hydroxide or potassium carbonate and the like by heating at the reflux temperature for from 6-90 hours, then recovering the product in a conventional manner with recrystallization from solvents such as n-propanol, isopropanol, absolute ethanol and the like.
TABLE IV 2-Amlno-4,5f6-substltuted Pyrimldinamines Ex. Acrylophenone Source Phenylguanldine Precursor Product MP°C 32 Ex. 12 Phenylguanldine carbonate 4-(2-Puranyl)-5-methyl-N-phenyl-2pyrimidinamine " 141-142 33 Ex. 3 (3-(Trifluoromethyl,phenylIguanidine carbonate 4-(4-Pvridiny1)-N-(3-(tri fluoromethyl) phenyl)-2-pyrimidinamine 198-200 34 Ex. 1 Phenylguanldine carbonate N-Phenyl-4-(3-pyridinyl)-2-pyrimidinamine 147-148 35 Ex. 1 (4-AcetyIpheny1)guanidine N-(4-AcetyIpheny1)-4-(3-pyridinyl)3-pyrimidlnamine 181-183 36 Ex. 1 (4-Fluorophenyl)guanidine carbonate N-(4-Pluorophenyl)-4-(3-pyridinyl)- 2-pyrimidlnamine 167-169 37 Ex. 11 (4-Methoxypheny1)guanidine carbonate N(4-Methoxyphenyl)-4-(2-pyridlnyl)2-pyrimidinamine 162-16438 Ex. 3 (4-FluorophenylIguanidine carbonate N-(4-Fluorophenyl)-4-(4-pyridinyl)2-pyrimidinamine 186-188 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 39 Ex. 1 (4-Bromophenyl)guanidine carbonate N-(4-Bromophenyl)-4-(3-pyridinyl)2-pyrimidinamine 174-175 40 Ex. 4 (4-Fluorophenyl)quanidine carbonate N-(4-Fluorophenyl)-4 -(2-thieny1)-2pyrimidinamine 176-178 41 Ex. 11 t3-(Trif1uoromethy1)phenylIguanidine carbonate 4-(2-Pyridinyl)-N-(3-(trifluoromethyl ) phenyl ] -2-pyrimidinamine 161-162 42 Ex. 4 Phenylguanidine carbonate N-Pheny1-4-(2-thieny1)-2-pyrimid inamine 137-139 43 Ex. 1 3-Chloro-4-methylphenylguanidine carbonate N-(3-Chloro-4-methylpheny1)-4-(3pyridinyl)-2-pyrimidinamine 140-145 44 Ex. 11 3-Methylphenylguaniidine carbonate N-(3-Methylphenyl)-4-(2-pyridinyl)2-pyrimidinamine 135-137 45 Ex. 3 3-Methylphenylguanidine carbonate N-(3-Methylphenyl)-4-(4-pyridinyl)2-pyrimidinamine 157-159 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 46 Ex. 3 Phenylguanidine carbonate N-Phenyl-*-(4-pyridinyl)-2-pyrimiHinamine 153-154 47 Ex. 1 3-Methylphenylguanidine carbonate N-(3-Methylphenyl)-4-(3-pyridinyl)2-pyrimidinamine 102-103 48 Ex. 3 4-Ethylphenylguanidine carbonate N-(4-Ethylphenyl)-4-(4-pyridinyl)3-pyrimidinamine 138-140 49 Ex. 13 4-Ethylphenylguanidine carbonate N-(4-EthyIpheny1)-5-methyl-4-(4pyridinyl)-2-pyrimidinamlne 132-133 50 Ex. 3 3,4-Dichlorophenylguanidine carbonate N-(3,4-Dichlorophenyl )-4-(4-pyridinyl )-2-pyrimidinamine 214-216 51 Ex. 1 4-Ethylphenylguanldine carbonate N-(4-EthyIpheny1)-4-(3-pyridinyl)2-pyrimidinamine 120-122.5 52 Ex. 11 4-BthyIphenylguanidine carbonate N-(4-Ethylphenyl)-4-(2-pyridinyl)2-pyrimidinamine 148.5-149.5 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 53 Ex. 4 3-Methylphenylguanidine carbonate N-(3-Methylphenyl)-4-(2-thienyl)1-pyrimidlnamine 112.5-114.5 54 Ex. 10 Phenylguanidine carbonate 4-(2-Purany1)-N-phenyl-2-pyrimidinamine ~ 144-145 55 Ex. 10 3-Methylphenylguanidine carbonate 4-(2-Furany1)-N-(3-methylphenyl)2-pyrimidinamine 98-99.5 56 Ex. 14 4-Ethylphenylguanidine carbonate N-(4-Ethylpheny1)-4-(6-me thy1-3pyridinyl)-2-pyrimidinamine 154-155 57 Ex. 15 4-Ethylphenylguanidine carbonate N-(4-Ethylphenyl)-6-methyl-4-(6methyl-3-pyridinyl)-2-pyrimidinamine 118-120 58 Ex. 16 4-Ethylphenylguanidine carbonate N(4-Ethylphenyl )-4 -(2-pyrazinyl)-2pyrimidinaming 157.5-159 59 Ex. 16 3-Methylphenylguanidine carbonate N-(3-Methylphenyl)-4 -(2-pyrazinyl)2-pyrimidinamine 112.5-117 ) TABLE IV (continued) Ex. Acrylophenone Source Phenylguanldine Precursor Product MP°C 60 Ex. 3 ✓ 2-Methylphenylguanidine carbonate N-(2-Methylphenyl)-4-pyra2inyl)-2pyrlmldinamine 129-130.5 61 Ex. 3 3-Ethylphenylquan1d1ne sulfate N-(3-Ethylphenyl)-4-(4-pyridinyl)3-pyrimidinamine 126-128 62 Ex. 3 2,5-Dimethylphenylguanidine carbonate N-(2,5-Dimethylpheny1)-4-(4-pyricfinyl-2-pyrimidinamine 131-134 63 Ex. 3 2,3-Dimethylhenylguanidine carbonate N-(2,3-Dlmethylphenyl)-4-(4-pyri3inyl)-2-pyrimidinamine 121-123 64 Ex. 17 3-Methylphenylguanidine carbonate N-(3-Methylphenyl)-4-(3-thienyl)2-pyrimidinamine 104.5-105.5 65 Ex. 11 2,5-Dimethylphenylguanidine carbonate N-(2,5-Dimethylpheny1)-4-(2-pyri3inyl)-2-pyrimidinamine 139-142 66 Ex. 3 3,5-Dimethylphenylguanidine carbonate N-(3,5-Dimethylpheny1)-4-(4-pyridinyl )-2-pyrimidinamine 183-185 -LTTABLE IV (continued) Ex. Acrylophenone Source Phenylguanidifte Precursor Product MP°C 67 Ex. 3 1-Naphthylguanidine nitrate N-l-Naphthalenyl-4-(4-pyridinyl)3-pyrimidinamine 174-176 68 Ex. 11 3,5-Dimethylphenylguanidine hydrochloride N-(3,5-Dimethylphenyl)-4-(2pyridinyl)-2-pyrimidinamine 114-119 69 Ex. 11 1-Naphthylguanidine nitrate Nrl-Naphthalenyl-4-(2-pyridinyl)?-pyrimidinamine 135-138 70 Ex. 3 2,4-Dimethylphenylguanidine carbonate N- (2,4-Dimethylpheny1)-4-(4-pyri3inyl)-2-pyrimidinamine 116-118 71 Ex. 3 2,4,6-Trimethylpheny1guanidine carbonate 4-(4-Pyridinyl)-N-(2,4,6-trimethy1phenyl)-2-pyrimidinamine 142-144 72 Ex. 10 4-Methoxyphenylguanidine carbonate 4-(2-Furanyl)-N-(4-methoxyphenyl)2-pyrimidinamine 155-158.5 73 Ex. 10 t3-(Trifluoromethyl)phenylJguanidine carbonate 4-(2-Furanyl)-N-[3-(trifluoromethyl jphenyl ]-‘2-pyrimidinamine 150-154 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanldine Precursor Product MP°C 74 Ex. 10 4-Pluorophenylguanidine carbonate N-(4-Pluorophenyl)-4-(2-furanyl)1-pyrimidlnamlne 150-152 75 Ex. 11 N-Cyolopentylguanldlne sulfate N-Cyclopentyl-4-(2-pyridinyl,-2pyrimidlnamlne 106-109 76 Ex. 11 3,4-DimethyIphenyIguanidine carbonate N- (3,4-Dimethylpheny1,-4-(2-pyriHinyl)-2-pyrimidinamine 130-133.5 77 Ex. 17 4-MethoxyphenyIguanidine carbonate N-(4-Methoxypheny1,-4-(3-thienyl)5-pyrimidinamine 158-160.5 78 Ex. 10 3-EthylphenyIguanidine sulfate N-(3-Ethylphenyl,-4-(2-furanyl)-2pyrimidinamine 95-98 79 Ex. 6 Phenylguanldine carbonate 4-(lH-Indol-3-y1)-N-phenyl-2pyrimldinamine 188-190 80 Ex. 3 2-Methoxy-5-methyIpheny1guanidine carbonate N-(2-Methoxy-5-methylphenyl)-4-(4pyridinyl)-2-pyrimidinamine 96-98.5 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 81 Ex. 20 3-Methylphenylguanidlne carbonate N-(3-Methylphenyl)-4-(1-methyl-lHpyrrol-2-yl)-2-pyrimidinamine " 117-120 82 Ex. 20 4-Ethylphenylquanidine carbonate N-(4-Ethylphenyl)-4-(1-methyl-lHpyrrol-2-yl)-2-pyrimidinamine 89-91 83 Ex. 20 Phenylguanidine carbonate 4-(l-Methyl-lH-pyrrol-2-yl)-Nphenyl-2-pyrimidinamine " 118-120 84 Ex. 4 3-EthyIphenylguanidine sulfate N-(3-Ethylphenyl)-4-(2-thienyl)-2pyrimidinamine 114-116 85 Ex. 17 3-Ethy1phenylguanidine sulfate N-(3-EthyIpheny1)-4-(3-thienyl)J-pyrimidinamine 86-89 86 Ex. 6 3-Methylphenylguanidine carbonate 4-(lH-Indol-2-yl)-N-(3-methylpheny1)-2-pyrimidinamine 164-167 87 Ex. 18 3-Methylphenylguanidine carbonate N-(3-Methylpheny1)-4-(4-quinolinyl)-2-pyrimidinamine 196-198 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 88 Ex. 18 Phenylguanidine carbonate N-Phenyl-4-(4-quinolinyl)-2-pyrimiSinamine 182-184 89 Ex. 18 4-EthylphenyIguanidine carbonate N-(4-Ethylphenyl)-4-(4-quinolinyl)3-pyrimidinamine 176-178 90 Ex. 10 3,5-DimethylphenyIguanidine hydrochloride N-(315-Dimethylphenyl)-4-(2-furanyl)-2-pyrimidinamine 126-129 91 Ex. 4 3,5-Dimethylphenylguanidine hydrochloride N-(3,5-Dimethylpheny1)-4-(2-thienyl)-2-pyrimidinamine. 152-155 92 Ex. 3 N-Me thy1-N-pheny1guan iSine hydrochloride N-Methyl-N-phenyl-4-(4-pyridinyl)2-pyrimidTnamine 105-107 93 Ex. 3 2,4-Dif1uoropheny1guanidine hydrochloride N-(2,4-Difluoropheny1)-4-(4-pyridinyl)-2-pyrimidinamine 172-174 94 Ex. 1 2,4-Difluorophenylguanidine hydrochloride N-(2,4-Di fluoropheny1)-4-(3-pyr idinyl)-2-pyrimidinamine 163-165 TABLE IV (continued) EX. Acrylophenone Source Phenylguanidine Precursor Product MP°C 95 Ex. 7 3-Methylphenylguanidine carbonate N-(3-Methylphenyl)-4-(5-methyl-2thlenyl>-2-pyrimidinamine 114-116 96 Ex. 3 2,6-Difluorophenylguanidlne hydrochloride N-(2,6-Di fluoropheny1)-4-(4-pyr i3inyl,-2-pyrimidinamine 174-176 97 Ex. 9 Phenylguanidine carbonate N-Phenyl-4-(lH-pyrrol-2-yl)-2pyrimidinamine 154-157 98 Ex. 1 4-Tert-butylphenylguanidine sulfate N-(4-(1,1-Dimethylethyl,phenyl)-4T3-pyridinyl,-2-pyrimidinamine 130-133 99 Ex. 1 2,6-Difluorophenylguanidine hydrochloride N-(2,6-Difluorophenyl)-4-(3-pyri3inyl,-2-pyrimidinamine 163-166 ).00 Ex. 7 3,5-Dimethylhenylguanidine hydrochloride N-(3,5-Dimethylpheny1)-4-(5-methy12-thienyl,-2-pyrimidinamine 133-135 101 Ex. 7 4-Ethylphenylguanidine carbonate N-(4-Ethylphenyl)-4-(5-methyl-2thienyl)-2-pyrimidinamine 123-125 -52TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 102 Ex. 11 3,4-Dimethylphenylguanidine hydrochloride N-((3,4-Dimethylphenyl)methyl]-4T2-pyridinyl)-2-pyrimidinamine 158-160 103 Ex. 7 3,5-Dimethylphenylquanidine hydrochloride N-(3,5-Dimethylphenyl)-4-(3-methy12-thienyl)-2-pyrimidinamine 151-155 104 Ex. 9 3-Methylphenylguanldine carbonate N-(3-Methylphenyl)-4-(lH-pyrrol-2yl)-2-pyrimidlnamine ~ 129-130 105 Ex. 8 3-Methylphenylguanidine carbonate 4-(5-Methyl-2-furanyl)-N-(3-methylpheny1)-2-pyrimidinamTne 119-121 106 Ex. 21 Phenylguanidine carbonate 4-Methyl-6-(5-methyl-2-thienyl)-Nphenyl-2-pyrimidinamine " 133-135 107 Ex. 3 4-(Dimethy1amino)pheny1guanidine dihydrochloride Ν-ί 4-(Dimethylamino)phenyl1-4-(4pyrldinyl)-2-pyrimidinamine 164-166 108 Ex. 3 3-Methoxyphenylguanidine hydrochloride N-(3-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine 159-160 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 109 Ex. 11 3-Methoxyphenylguanidine hydrochloride N-(3-Methoxyphenyl)-4-(2-pyridinyl)-2-pyrimidinamine 110-113 no Ex. 11 4-(Dimethylamino)phenylguanidine dihydroohloride N-[4-(Dimethylamino)phenyl1-4-(2pyridinyl)-2-pyrimidinamine 171-174 111 Ex. 1 3-Methoxyphenylguanidine hydrochloride N-(3-Methoxyphenyl)-4-(3-pyridinyl )-2-pyrimidinamine 126-127 112 Ex. 1 3,5-Dimethylphenylguanidine hydrochloride N-(3,5-Dimethylphenyl)-4-(3-pyri3inyl)-2-pyrimidinamine 125-128 113 Ex. 1 4-(Ethoxycarbonyl)phenylguanidine hydrochloride 4-((4-(3-Pyridinyl)-2-pyrimidinyl)amino]benzoic acid, ethyl ester 197-202 114 Ex. 1 4-(Dimethylamino)phenyl- quanidine dihydrochloride • N,N-Dimethy1-N*-(4-(3-pyridiny1)2-pyrimidiny ΓΤ-1,4-benzenediamine 165-166 115 Ex. 22 Phenylguanidine carbonate 4-(2,5-Dimethyl-3-furanyl)-Nphenyl-2-pyrimidinamine ~ 116-118 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 116 Ex. 17 4-EthyIphenylguanidine carbonate N-(4-Ethylphenyl)-4-(3-thienyl)-2pyrimidinamine 151-152.5 117 Ex. 22 3-Methylphenylguanidlne carbonate 4-(2,5-Dimethyl-3-furanyl)-N-(3methy1phenyl)-2-pyrimidinamTne 144-146 116 Ex. 22 3,5-Dimethylphenylguanidine hydrochloride 4-(2,5-Dimethyl-3-furanyl)-N-(3,5dimethylphenyl)-2-pyrimidinamine 149-152 119 Ex. 22 4-Ethylphenylguanidine carbonate 4-(2,5-Dimethyl-3-furanyl)-N-(4 ethylphenyl)-2-pyrimidinamlne 93-96 120 Ex. 1 3-Dime thy1ami nophenylguanidine dihydrochloride N,N-Dimethyl-N'-(4-(3-pyridinyl)-2pyrimidinyl)-T,3-benzenediamine 123-125 121 Ex. 11 3-(Ethoxycarbony1)phenylguanidine hydrochloride 3-1,( 4-(2-Pyridinyl )-2-pyrimidinyl )amino]benzoic acid, ethyl eater 156-158 122 Ex. 11 3-(DimethylaminoIpheny1guanidine dihydrochloride N,N-Dimethy1-N*-(4-(2-pyridinyl)-2pyrimidinylJ-T,3-benzenediamine 109-111 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanldine Precursor Product MP°C 123 Ex. 1 3-(Ethoxycarbonyl)phenylguanidine hydrochloride 3-((4-(3-Pyridinyl)-2-pyrimidinyl)amino1benzoic acid, ethyl ester 95-103 124 Ex. 10 4-(Dimethylamino)phenylguanidine dihydrochloride N*-(4-(2-Furany1)-2-pyrimidinyl)N,N-dimethyl-l,4-benzenediamine 166-167 125 Ex. 4 4-(Dimethylamino)phenylguanidine dihydrochloride N,N-Dimethyl-Ν’-(4-(2-thienyl)-2pyrimidinyl)-T,4-benzenediamine 174-175 126 Ex. 22 4-(Dimethylamino)phenylguanidine dihydrochloride Ν'-(4-(2,5-Dimethy1-3-furany1)-2pyrImidinyl1-Ν,Ν-dimethyl-1,4benzenediamine 126-129 127 Ex. 19 4-(Dimethylamino)phenylguanidine dihydrochloride N,N-Dimethyl-N'-(4-(3-methyl-2thTenyl)-2-pyrimidiny1)-1,4benzenediamine 145-148 128 Ex. 3 3-(Dimethylamino)phenylguanidine dihydrochloride N,N-Dimethyl-Ν'-(4-(4-pyridlny1)-2pyrimidinyl)-T,3-benzenediamine 165-168 129 Ex. 12 3,5-DimethylphenyIguanidine N-(3,5-Dimethylphenyl)-4-(2-furany 1 )-5 -methy 1-2-pyrimidinamine 155-158 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanldine Precursor Produot MP°C 130 Ex. 12 4-(Dimethylaminolpheny1guanidine dihydrochloride N‘"14-(2-Furanyl)-5-methyl-2pyrimidinyl]-N,N-dimethyl-1,4benzenediamine "* 146-148 131 Ex. 29 4-(Dimethy1amino)phenylguanidine dihydrochloride N’-(4-(2-Benzofuranyl)-2-pyrimi3inyll-N,N-dimethyl-l,4-benzenediamine** " 175-178 132 Ex. 11 2-Guanidinobensimida2ole N-(4-(2-Pyridlnyl)-2-pyrimidinyl]- TH-benzimldazol-2-amine 276-279.5 132 Ex. 23 Phenylguanldine carbonate 4-Methyl-N-phenyl-6-(2-pyridinyl)2-pyrimidTnamine 94-98 134 Ex. 4 3-(Dimethylamino)phenylguanidine dihydrochloride Ν,Ν-Dimethyl-N'-(4-(2-thieny1)-2pyrimidinyl]-T,3-benzenediamine 118-120 135 Ex. 8 3-(Dimethylamino)pheny1quanidine dihydrochloride N,N-Dimethyl-N’-(4-(5-methyl-2furany1)-2-pyrimidinyl1-1,3-benzenediamlne 126-129 136 Ex. 22 3-(Dimethy1amino)pheny1guanidine dihydrochloride N*-(4-(2,5-Dimethyl-3-furanyl)-2pyrimidinyl)-N,N-dimethyl-l,3benzenedlamlne ~ 153-155 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 137 Ex. 3 4-AminoacetylphenyIguanidine hydrochloride N-(4-([4-(4-Pyridinyl)-2-pyrimidinyl) ami no] phenyl ]acetamide 294-296 138 Ex. 3 4-(Diethylamino)phenylguanidine dihydrochloride N,N-Diethyl-N'-(4-(4-pyridinyl)S-pyr imidinyl )-1,4-benzenediamine 126-128 139 Ex. 1 4-(Diethylamino)phenylguanidine dihydrochloride Ν,Ν-Diethy1-N'-(4-(3-pyridiny1)5-pyrimidlnyT]-1,4-benzenediamine 100-104 140 Ex. 17 Phenylguanidine carbonate N-Phenyl-4-(3-thienyl)-2-pyrimidinamine 142-143 141 Ex. 11 4-PluorophenyIguanidine carbonate N-(4-Pluorophenyl)-4-(2-pyridinyl)?-pyrimidinamlne 207-209 142 Ex. 11 4-ChlorophenyIguanidine carbonate N-(4-Chlorophenyl )-4-(2-pyridinyl)3-pyrimidinamine 220-222 143 Ex. 3 4-MethylphenyIguanidine carbonate N-(4-Methylphenyl)-4-(4-pyridinyl)2-pyrimidinamine 197.5-198.5 -53TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 144 Ex. 31 N-(3-(Trifluoromethyl)phenyllguanidine carbonate 4-(2-Phenothiazine)-N-(3-( trifluoromethyl) phenyl J-2-pyrimidlnamine 240-243 145 Ex. 31 4-Methoxyphenylguanidine carbonate N-(4-Methoxyphenyl)-4-(2-phenothiazine)-2-pyrimidinamine 220-225 146 Ex. 31 3,4-Dichlorophenylguanidine carbonate N-(3,4-Dichloropheny1)-4-(2-phenothiazine)-2-pyrimidinamine 235-238 147 Ex. 11 2,4-Dimethylphenylguanidine carbonate N-(2,4-Dimethylpheny1)-4-(2-pyri3inyl)-2-pyrimidinamine 111.5-113.5 148 Ex. 3 2-Me thoxyphenylguan id i ne carbonate N-(2-Methoxyphenyl)-4-(4-pyridinyl )-2-pyrimidinamine 112-117 149 Ex. 3 2,5-Dimethoxyphenylguanidine carbonate N-(2,5-Dimethoxypheny1)-4-(4-pyr idinyl1-2-pyrimidinamine 151.5-155.0 150 Ex. 11 2-Methoxy-5-methy1pheny1guanidine carbonate N-(2-Methoxy-5-methyIpheny1)-4-(2pyridinyl)-2-pyrimidinamine 117-118.5 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine' Precursor Product MP°C 151 Ex. 3 3,4-Dimethylphenylguanidine hydrochloride N-I(3,4-Dimethylpheny1)methyl]-4T4-pyridinyl)-2-pyrimidinamine 132-136 152 Ex. 29 3-Methylphenylguanidine carbonate 4-(2-Benzofuranyl)-N-(3-methylphenyl)-2-pyrimidinamine 143-144 153 Ex. 3 3,4-Dimethylphenylguanidine carbonate N- (3,4-Dimethylpheny1)-4-(4-pyriHinyl)-2-pyrimidinamine 169-171.5 154 Ex. 17 4-Fluorophenylguanidlne carbonate N-(4-Fluorophenyl)-4-(3-thienyl)I-pyrimidinamine 185-187 155 Ex. 31 Phenylguanidine carbonate 4-(10H-Phenothia2ln-2-yl)-NphenyT-2-pyrimidinamine ~ 218-220 156 Ex. 6 4-Ethylphenylguanidine carbonate * N-(4-Ethylpheny1)-4-(1H-indol-3yl)-2-pyrimidinamine ~ 209-210 157 Ex. 3 1,1'-Biphenylguanidine hydrochloride N-(l,1'-Biphenyl]—4 —yl—4-(4-pyridinyl )-2-pyrimidinamine 203-205 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 158 Ex. 3 (4-(1,1-Dimethylethyl,phenylIguanidine sulfate N-(4-(1,1-Dimethylethyl,phenyl]ϊ-(4-pyridinyl,-2-pyrimidinamine 181-183 159 Ex. 11 N-Methyl-N-phenylguani3ine hydrochloride N-Methyl-N-phenyl-4-(2-pyridinyl)2-pyrimidTnamine 88-91 160 Ex. 9 4-EthylphenyIguanidine carbonate N-(4-Ethylphenyl,-4-(lH-pyrrol-2yl,-2-pyrimidinamine " 131-133 161 Ex. 19 Phenylguanidine carbonate 4-(3-Methyl-2-thieny1,-N-pheny12-pyrimidinamine 137-140 162 Ex. 25 4-Dimethylaminophenylguanidine dihydrochloride N,N-Dimethyl-N'-(4-methyl-6-(4- pyridinyl,-2-pyrlmidinyll-l,4- benzenediamine 153-154 163 Ex. 26 3,5-Dimethylphenylguanidine hydrochloride N-(3,5-Dimethylpheny1,-4-methy1-6T3-pyridinyl,-2-pyrimidinamine 136-140 164 Ex. 12 N-l3-(Trifluoromethyl,phenylIguanidine carbonate 4-(2-Puranyl,-5-methyl-N-i3-(trifluoromethyl ,phenyl1-2-pyrimidinamine 169-171 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 165 Ex. 23 N-(3,5-Dimethylpheny1)guanidine N-(3,5-Dimethylphenyl)-4-methyl-6T2-pyridinyl)-2-pyrimidinamine 110-112 166 Ex. 10 2-Guanidinobenzimidazole N-[4-(2-Furany1)-2-pyrimidinyl)ΙΗ-benzimidazol-2-amine 306.5-308 167 Ex. 23 N-[4-(D ime thylami no)phenyl]guanidine dihydrochloride N,N-Dimethyl-N·-(4-methyl-6-(2pyridinyl)-2-pyrimidinyl)-1,4benzenediamine 145-148 168 Ex. 3 4-(1-Imidazolyl)phenylguanidine dihydrochloride N-l4-(lH-Imidazol-l-yl)phenyl )-4T4-pyri3inyl)-2-pyrimidinamine >320 169 Ex. 30 ,4-(l*Imidazolyl)phenylguanidine dihydrochloride N-(4-(lH-Imidazol-l-ylJphenyl)-4T3-pyridinyl)-2-pyrimidinamine 134-174 (Dec.) 170 Ex. 11 N-[4-Diethylamino)phenyljguanidine dihydrochloride N,N-Diethyl-N'-[4-(2-pyridinyl)-2pyrimidiny1)-1,4-benzenediamine 138-139 171 Ex. 11 4-(1-Imidazolyl)phenylguanidine dihydrochloride N-(4-(ΙΗ-Imidazol-l-yl)phenyl )-4T2-pyridinyl)-2-pyrimidinamine 204-206 -62TABLE IV (continued) Ex. Acrylophenone Source Phenylguanldine Precursor Product MP°C 172 Ex. 10 4-(l-ImidazolylJphenylguanidine dihydrochloride 4-(2-Puranyl)-N-[4-(lH-imidazol-1ylIpheny1I-2-pyrimidinamine 211-212.5 173 Ex. 12 N-(3-Dlmethylamino)phenyliguanidine dihydrochloride N,N-Dimethyl-N’-(4-(2-furanyl)-5methyl-2-pyrimidinyl1-1,3-benzenediamine 154-156 174 Ex. 21 N-(3-Dimethylamino)phenyl Iguanidine dihydrochloride Ν,Ν-tDlmethyl-N’ -(4-( 5-methyl-2thTenyl)-2-pyrimidinyl1-1,3-benzenediamine 130-133 175 Ex. 17 N-14 -. (D ime thy 1 ami no) phenylIguanidine dihydrochloride N,N-Dimethyl-N'-(4-(3-thienyl)-2pyrimidinyl]-T,4-benzenediamine 173-174 176 Ex. 13 N-(3-(Dimethylamino)phenyl Iguanidine dihydrochloride N,N-Dimethyl-N‘-(4-methyl-6-(4pyridinyl)-2-pyrimidinyl1-1,3benzenediamine 200-201 177 Ex. 4 4-(l-Imida2olyliphenylguanidine hydrochloride N-(4-(lH-lmidazol-l-ylJphenyl1-4?2-thieny11-2-pyrlmldlnamine 179-189 (Dec.) 178 Ex. 19 N-(3-Methoxypheny1Iguanidine hydrochloride N-(3-Methoxyphenyl)-4-(3-methyl-2thienyl,-2-pyrimidinamine 120-123 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 179 Ex. 30 N-(4-(Acetylamino)phenyl Iguanidine hydrochloride N-(4-((4-(3-Pyridinyl)-2-pyrimidinyl)amlno]phenyllacetamide 192-195 180 Ex. 30 N-(4-Benzenesulfonamido)guanidine hydrochloride 4-((4-(3-Pyridinyl)-2-pyrimidinyl]aminoIbenzenesuIfonamide 224-225 181 Ex. 3 N-(3-Chlorophenyliguanidine carbonate N-(3-Chlorophenyl)-4-(4?-pyridinyl)- 2-pyrimidinamine 160-161 182 Ex. 30 N-(3-Chlorophenyl)guaniSine carbonate N-(3-Chlorophenyl)-4-(3-pyridinyl)2-pyrimidinamine 146-148 183 Ex. 17 N-(3-Methoxyphenyliguanidine hydrochloride N-(3-Methoxyphenyl )-4-(3-thienyl)2-pyrimidinamine 142-145 184 Ex. 4 N-(3-Methoxyphenyliguanidine hydrochloride N-(3-Methoxyphenyl)-4-(2-thienyl)1-pyrimidinamine 151-153 185 Ex. 30 [4-(acetylmethylamino) phenyl]guanidine hydrochloride N-Methyl-N-(4-((4-(3-pyridinyl)-2p:rimldinyl] amine 1phenyl lacetamide 194-197 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 186 Ex. 3 [4-(acetylmethyl ami no) phenyllguanidine hydrochloride N-Methy1-N-(4-((4-pyridinyl)-2pyrimidinyl]amino]phenyl]acetamide 233-234 187 Ex. 11 [4-(acetylmethyl ami no) phenyl]guanidine hydrochloride N-Methyl-N-14-( 14-(2-pyridinyl)-2pyrimidinyllaminoIpheny1]acetamide 179-181 188 Ex. 10 N-(3-Methoxypheny1)guani3ine hydrochloride 4-(2-Furanyl)-N-(3-methoxyphenyl )2-pyrimidinamine 114-116 189 Ex. 29 N-(3-Methoxyphenyllguanidine hydrochloride 4-(2-Benzofuranyl)-N-(3-methoxypheny 1 ) -2-pyr imidinamine 137 190 Ex. 9 N-(EthyIpheny1lguanidine carbonate N-(4-Ethylphenyl)-4-(1-methyl-lHpyrrol-2-yl)-2-pyrimidinamine ~ 89-91 191 Ex. 3 N-AcetyIphenylguanidine hydrochloride N-(4-((4-(4-Pyridinyl)-2-pyrimidinyljamino)phenylJacetamide 294-296 192 Ex. 10 N,N-DimethyIphenylguanidine dihydrochloride N,N-Dimethy1-N’-(4-(2-furanyl)-5methyl-2-pyrimidinyl1-1,3-ben2enediamine 154-156 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 193 Ex. 30 N-Acetylphenylguanidine Hydrochloride N-I4-( 14-(3-Pyridinyl)-2-pyrimidinyllaminolpheny1lacetamide 192-195 194 Ex. 11 Sulfonylaminophenylguanidine hydrochloride 4-1(4-(2-Pyridinyl)-2-pyrimidinyl]amino]benzenesulfonamide 274-277 195 Ex. 11 N-Acetylphenylguanidine Hydroch1oride N-(4-((4-(2-Pyridinyl)-2-pyrimidinyllaminoIphenyllacetamide 254-255 196 Ex. 4 3-Methoxyphenylguanidine hydrochloride N-(3-Methoxyphenyl)-4-(2-thienyl)2-pyrimidinamine 151-153 197 Ex. 30 4-(4-Methylpiperazin-lyl)phenylguanidine dihydrochloride N-{4-(4-Methyl-l-piperazinyl)phenyll-4-(3-pyridinyl)-2-pyrimidinamine 174-175 198 Ex. 7 3-Methoxyphenylguanidine hydrochloride* N-(3-Methoxypheny1)-4-(5-me thy1-2thienyl)-2-pyrimidinamine 149-151 199 Ex. 11 3-Chlorophenylguanidine hydrochloride N-(3-Chlorophenyl)-4-(2-pyridinyl)2-pyrimidinamine 164-165 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanldine Precursor Product MP°C 200 Ex. 10 4-(4-Methylpiperazln-lyl)phenylguanldine dihydrochloride 4-(2-Furanyl)-N-(4-(4-methyl-lpipera2inyl)pheny11-2-pyrimidinamine 193-195 201 Ex. 4 4-(4-Methylpipera2in-lyl)phenylguanldine dihydrochloride N-[4-(4-Methyl-l-piperazinyl)phenyll-4-(2-thienyl)-2-pyrimidinamine 215.5-216.5 202 Ex. 11 4-(4-Methylplperazin-lyljphenylguanidine dihydrochloride N-[4-(4-Methyl-l-pipera2inyl)phenyll-4-(2-pyridinyl)-2-pyrimidinamlne 192-193 TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C • 203 Ex. 13 4-(4-Methylpiperazin-lyl)phenylguanidine dihydrochloride H-(4-(4-Methyl-l-piperazinyl)phenyl)-4-(4-pyridinyl) -2pyrimidinamine 207-209 204 Ex. 2 2 3-MethoxyphenyIguanidine hydrochloride U-(3-Methoxyphenyl)-4-(2,5-dimethyl-3-furanyl)-2-pyrimidinamine 124-125 205 I . Ex. 13 3-FluorophenyIguanidine hydrochloride H-(3-Fluorophenyl)-4-(4-pyridinyl) 2-pyrimidinamine 162 ; 206 L... Ex. 30 3-FluorophenyIguanidine hydrochloride U-(3-Fluorophenyl)-4-(3-pyridlnyl)2-pyrimidinamine 147-150 1 1 207 Ex. 11 3-FluorophenyIguanidine hydrochloride H-(3-Fluorophenyl)-4-(2-pyridinyl)2-pyrimidinamine 162-164 208 Ex. 3 0 4-Acetyl phonyIguanidine 1-(3-((4-(3-Pyridinyl)-2-pyrimid iny1)amino]phenyl]ethanone 166-168 -68TABLE IV (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 209 Ex. 30 1-(Methylethyl)phenylguanidino hydrochloride M-[4-(l-Methylethyl)phenyl]-4-(3pyridinyl)-2-pyrimidinamine 124-125 210 Ex. 30 3-Ethylphenylguanidlne hydrochloride U-(3-Ethylphenyl)-4-(3-pyridinyl)2-pyrimidinamine 80-88 211 Ex. 11 3-EthyIphenylguanidine hydrochloride H-(3-Ethylphenyl)-4-(2-pyridinyl) 2-pyrlmidinamine 101-104 212 Ex. 11 3-Benzenesulfonamidoguanidine hydrochloride 3-((4-(2-Pyridinyl)-2-pyrimidinyl)aminoJbenzenesulfonamide 223-225 213 Ex. 30 3-Benzenesulfonamidoguanidine hydrochloride 3-((4-(3-Pyridinyl)-2-pyrimidinyl)amino)benzenesu1fonamide 278-280 214 Ex. 24 4-(1,1-Dimethylethyl)phenylguanidine hydrochloride N-[4-(1,1-Dimethylethy1) phenyl)-4(2-thienyl)-2-pyrimidinamine 150-154 215 Ex. 10 4-(Diethylamino)phenylguanidine hydrochloride H#N-Diethyl-N1-[4-(2-furanyl)-2pyrimidinyl)-1,4-benzenediamine 132-133 TABLE IV (continued) Ex, 216 ί 217 218 219 220 221 rylophenone Source Phenylguanidine Precursor 1 Product MP°C Ex. 13 4-Benzenesulfonamidoguanidine hydrochloride 3-((4-(4-Pyridinyl)-2-pyrimidinyl]amino]benzenesulfonamide 262-264 Ex. 13 4-Acetylaminophenylguanidine hydrochloride H"(3-((4-(4-Pyridinyl)-2-pyrimidinyl ]amino]phenyl]acetamide 267-270 Ex. 30 4-Acetylaminophenylguanidine hydrochloride H-(3-((4-(3-Pyridinyl)-2-pyrimidi nyl ] amino ] pheny 1 ] acetamide 239-241 Ex . 11 3-Acetylaminophenylguanidine hydrochloride 14-(3-( (4- (2-Pyridinyl) -2-pyrimidiny 1] amino] pheny 1 ] acetamide 190-192 Ex. 13 3-(ΙΗ-Imidazol-l-yl)phenylguanidine dihydrochloride H-(3-(ΙΗ-Imidazol-l-yl)phenyl]-4(4-pyridinyl)-2-pyrimidinamine 232-234 Ex. 13 4-Acetylamino-3-methylphenylguanidine hydrochloride N-(2-Methyl-4-((4-(4-pyridinyl)-2pyrimidinyl]amino]phenyl]acetamide 230-235 Ex. 21 4-Acetylaminophenylguanidine hydrochloride H-(4-[(4-(5-Methyl-2-thienyl)-2pyrimidiny1]amino]phenyl]acetamide 227-230 TABLE IV (continued) Ex. 223 224 225 : 226 : 227 228 | i Acrylophenone Source Phenylguanidine Precursor Product MP°C Ex. 30 3-(2-(Diethylaminoethoxy) phenyllguanidine dihydrochloride (3-(2-(Diethylamino)ethoxy)phenyl ]-4-(3-pyridinyl) -2-pyrimidinamine 79-82 Ex. 30 2-Methoxyphenylguanidine carbonate H-(2-Methoxypheny1)-4-(3-pyr id i nyl)-2-pyrimidinamine 99-101 EX. 24 4-Acetylaminophenylguanidine hydrochloride H"(4-((4-(2-Thienyl)-2-pyrimidinyl ] amino] phenyl ]acetamide 201-203 Ex. 30 4-Acetylamino-3-methy1phenylguanidine hydrochloride h}-[ 2-Methy 1-4-( 4- (3-pyridinyl) -2pyrimidinylIphenyllacetamide 233-235 Ex. 29 4-!Diethylaminophenylgunnldino hydrochlorido H'-(4-(2-Benzofuranyl)-2-pyrimidinyl ]-N,N-diethyl-l, 4-benzenediamine 134-136 Ex. 12 4-Acetylaminophenylguanidine hydrochloride N-(4-[(4-(2-Furanyl)-2-pyrimidinyl]amino]phenyl]acetamide 230-232 TAPkELIY.. (continued) Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 229 Ex. 13 4-(Imidazol-l-yl)-3(trifluoromethyl)phenylguanidine dihydrochloride N-(4-(lH-Imidazol-l-yl)-3-(trifluoromethyl) phenyl]-4-(4-pyridinyl) -2-pyrimidinamine 238-239 230 • EX. 11 1 4-Acetylamino-3-methylphonylguanidine hydrochloride H"[2-Methyl-4-((4-(2-pyridinyl)-2pyrimidiny1]amino]phony1) acetamide 232-234 231 .. Ex. 30 ·· 3-(1-Imidazolyl)phenylguanidine dihydrochloride M"(3-(ΙΗ-Imidazol-l-yl) phenyl )-4(3-pyridinyl)-2-pyrimidinamine 137-144 232 Ex. 24 3-(1-Imidazolyl)phenylguanidine dihydrochloride M-(3-(lH-Imidazolyl)phenyl]-4-(2thienyl)-2-pyrimidinamine 183-184.5 233 . EX. 10 3-(1-ImIdazolyl)phenyl- 4-(2-Furanyl)-N-(3-(lH-imidazol-1- 160-168 guanidine dihydrochloride yl)phenyl]-2-pyrimidinamine TABLE IV (continued) Ex . Acrylophenone Source Phenylguanldine Precursor Product MP°C 234 Ex. 10 3-(Diethylamino)ethoxyphenylguanidine dihydrochloride H-(3-(2-(Diethylamino)ethoxy)phenyl )-4-(2-furany1)-2-pyrimidinamine 235 Ex. 10 3-Methylphenylguanidine hydrochloride 4-(2-Furanyl)-N-(3-methylphenyl)-2pyrimidinamine7 hydrochloride 195-199 236 Ex. 11 4-(1-Imidazolyl)-3-(trifluoromethyl ) phenylguanidine dihydrochloride M-(4-(lH-Imidazol-l-yl)-3-(trifluoromethyl)phenyl)-4-(2-pyridinyl) -2-pyrimidinamine 216-218 237 Ex. 2 4 3-(Diethylamino)ethoxyphenylguanidine dihydrochloride U-(3-(2-(Diethylamino)ethoxy) phenyl )-4-(2-thienyl)-2-pyrimidinamine 238 Ex. 10 4-Benzenesulfonamidoguanidine hydrochloride 4-((4-(2-Furanyl)-2-pyrimidinyl)amino]benzenesulfonamide 255-257 239 Ex. 21 4-Benzenesulfonamidoguanidine hydrochloride 4-[(4-(5-Methy1-2-thienyl)-2pyrimidinyl) amino]benzenesulfonamide 241-245 TABLE IV (continued) "Ί Ex. — 240 I Acrylophenone Source Phenylguanldine Precursor Product MP°C Ex. 17 [4-(acetylmethy1 ami no) phenyljguanidine hydrochloride H-Methy1-N-(4-((4-(3-thienyl)-2pyrimidinylJaminoJphenyl]acetamide 150-153 1 241 Ex. 13 ... 3-[4-Mfethyl-1-piperazinyl Iphenylguanidine hydrochloride U-(3-(4-Methyl-1-piperazinyl)phenyl )-4-(4-pyridinyl)-2-pyrimidlnamine 150-151.5 242 Ex. 10 3-(4-Methyl-l-piperazinyl)phenylguanldine hydrochloride 4-(2-Furany1)-N-(3-(4-methyl-1piperazinyl)phenyl]-2-pyrimidinanine 134.5-136 243 Ex. 24 3-(4-Methyl-l-piperazinyl )phenylguanldine hydrochloride U-(3-(4-Methyl-1-piperazinyl)phenyl )-4- (2-thienyl )-2-pyrimidinamine 125-126.5 244 Ex. 13 2-Dimethylaminophenylguanidine dihydrochloride H,N-Dimethy1-N'-[4-(4-pyridinyl)-2pyrimidinyl]-1,2-benzenediamine 114-119 TABLE...ΐν_( continued! Ex. Acrylophenone Source Phenylguanidine Precursor Product MP°C 245 Ex. 13 3-(Diethylamino)ethoxyphenylguanidine dihydrochloride 3-[2-(Diethylamino)ethoxy]phenyl )-4- (4 -pyridinyl) -2 -pyr imidinamine 100-103 246 Ex. 24 3-(Diethylamino)ethoxypheny lguanidine dihydrochloride M"[4-[2-(Diethylamino)ethoxy)phenyl ] -4- (2-thienyl) -2-pyrimidinamine 247 Ex. 24 3-(Dimethylamino)ethoxyphenylguanidine dihydrochloride [4-12-(Dimethylamino)ethoxy]phenyl ]-4- (2-thienyl) -2-pyrimidinamine 96-98 248 . Ex. 17 3-(Dimethylamino)ethoxyphenylguanidine dihydrochloride H-(4-(2-(Dimethylamino)ethoxy]phenyl ] -4- (3-thienyl) -2-pyrimidinamine 83-85 249 Ex. 21 4-Diethylaminophenylguanidine hydrochloride H,N-Diethyl-N·-(4-(5-methy1-2-furanyl) -2-pyrimidinyl ]-l ,4-benzenediamine 118-119 250 EX. 21 3-Methoxyphenylguanidine hydrochloride (3-Methoxyphenyl)-4-(5-methy1-2furanyl)-2-pyrimidinamine 251 EX. 13 3- (lH-Imid azol-l-yl)phenylguanidine dihydrochloride N-[3-(lH-Imidazol-l-yl)phenyl]-4-(4-pyridinyl)-2-pyrimidinamine J 232-239 _ -76Example 252 1-(4-([4-(3-Pyridiny1)-2-pyrimidinyl)aminoJpnenyl]ethanone, oxime A 2.03 mg portion of N-(4-acetylphenyl)-4-(3pyridinyl)-2-pyrimidinamine was mixed with 210 ml of absolute ethanol and 1.26 g of hydroxylamine hydrochloride. An 18.2 ml portion of IN sodium hydroxide was added, the mixture was heated at reflux for 2 hours and then evaporated to 1/4 volume. This was cooled, the solid collected, washed with ethanol and water and dried, giving 1.9 g of the desired product as cream colored crystals, mp 239241°C.
Example 253 1-(4-([4-(3-Pyridinyl)-2-pyrimidinyllamino1phenyl]ethanone, O-methyloxime The procedure of Example 252 was repeated using methoxyamine hydrochloride, giving 1.78 g of the desired product as yellow crystals, mp 163-167°C.
Example 254 N—(1—(4—((4—(3-Pyridiny1,-2-pyrimidinyl1amino1phenyl]ethyl1formamide A mixture of 7.25 g of N-(4-acetylphenyl,-4-(3pyridinyl)-2-pyrimidinamine, 100 ml of formamide and 31 ml. of 98% formic acid was refluxed with stirring overnight. The solvents were then boiled off for 1/2 hour, the reaction cooled and poured into one liter of water. This was extracted with 725 ml of chloroform. The chloroform extract was back washed with 150 ml of water, then dried, filtered and evaporated to a foam. The foam was partitioned between chloroform and water. An equal volume of saturated potassium bicarbonate was added. The organic phase was separated, dried, filtered and evaporated to a foam. This foam was chromatographed on silica gel topped with a thin layer of hydrous magnesium silicate and eluted with chloroform (first four fractions), then with 2% methanol in chloroform (last two fractions). The sixth -77(final) fraction was evaporated and then crystallized from chloroform-hexane, giving 1.05 g of the desired product as cream colored crystals, mp 118-121°C.
Example 255 N—(4—(2—(Dimethylamino) ethoxy ] phenyl ] -4 - (3-pyridinyl) 2-pyrimidinamine A 1.10 g portion of dry 4-( (4-(3-pyridinyl)2-pyr imidinyl Jamino J phenol was dissolved in 2S ml of dimethylformamide. A 213 mg portion of sodium hydride (50% in oil) was added, the reaction was sealed and stirred for 45 minutes. A 480 mg portion of 2-dimethylaminoethyl chloride in 2 ml of dimethylformamide was added and the sealed mixture was stirred overnight. The solvent was removed at 60°C and the residue partitioned between 25 ml of water and 50 ml of ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with IN sodium hydroxide, dried, filtered and evaporated. The residue was taken up in 20 ml of chloroform, boiled down to 1/3 volume and hexane added to turbidity. The mixture was allowed to stand overnight, giving 400 mg of the desired product as beige crystals, mp 108-110°C.
Example 2 56 N-(4-(3-(Dimethylamino) propoxy lpheny 11-4-( 3-pyridinyl) 2-pyrimidinamine A 5.46 g portion of 4-((4-(3-pyridinyl)-2pyrimidinylJamino1phenol was reacted with 3-dimethylaminopropyl chloride by the procedure of Example 255, giving 2.9 g of the desired product, mp 85-87OC.
Example 257 N-[4-[ 2-(Diethylamino)ethoxy Iphenyl 1-4-(4-pyridinyl )2-pyrimidinamine The procedure of Example 256 was repeated using 4-((4-(4-pyridinyl)-2-pyrimidinyl1amino1phenol, giving 300 mg of the desired product as yellow crystals, mp 8587°c. -78Example 258 N-(4-(2-(DiethylaminoJethoxylpheny1]-4-(3-pyridinyl)2-pyrimidinamine The procedured of Example 255 was repeated, using 2-diethylaminoethyl.chloride, giving 3.45 g of the desired product as yellow crystals, mp 87-89°C.
Example 259 N-(4-(2-( Dime thylamino) ethoxy ] pheny 1 ] -4 - (4 -py r idiny 1) 2-pyrimidinamine The procedure of Example 255 was repeated using 4-((4-(4-pyridinyl)—2-pyrimidinyl]amino]phenol, giving 1.6 g of the desired product as yellow crystals, mp ΙΣΟΙ 22°C.
Example 2 60 N— (4—(2- (Dimethylamino)ethoxy ] phenyl ] -N*,N ’ dimethyl-N-I4-( 4-pyridinyl) -2-pyrimidinyl ] -1,2-. ethanediamine The procedure of Example 259 was repeated. Subsequent crops of crystals gave 0.4 g of the desired product, mp 87-91°C.
Example 261 N- [ 4 - [ 3 - (Dimethylamino) propoxy 1 phenyl ] -4 - (4 -pyridinyl) 2-pyrimidinamine A 2.78 g portion of 4-((4-(4-pyridinyl)-2pyrimidinyl]amino]phenol and 2.35 g of 3-dimethylaminopropyl chloride were reacted as described in Example 255, giving 850 mg of the desired product, mp 123-124.5°C.
Example 262 [4-( (4-( 4-Pyridinyl )-2-pyrimidinyl ]amino]phenoxy]acetic acid, ethyl ester A mixture of 5.58 g of 4-((4-(4—pyridinyl)-2pyrimidinyl]amino]phenol was reacted with ethyl bromo acetate as described in Example 255, giving 1.8 g of the desired product as yellow crystals, mp 109-llloc. -79Example 263 N-(4-Methoxyphenyl )-N-methyl-4-(3-pyridinyl)-2pyrimidinamine A 2.70 g portion of N-(4-methoxyphenyl)-4(3-pyridiny 1)-2-pyrimidinamine was dissolved in 30 ml of dimethylformamide. A 528 mg portion of sodium hydride (50% in oil) was added, the reaction sealed and stirred for 45 minutes. A solution of 1.70 g of methyl iodide in 2 ml of dimethylformamide was added, the sealed mixture was stirred overnight and the solvent removed. The residue was partitioned between water and chloroform. The organic phase was dried, filtered arid evaporated. 'The residue was crystallized from ether-hexane giving 1.4 g cf the desired product as yellow crystals, mp eS-9C°C.
Example 264 N- (4 -Methoxyphenyl) -N-methyl-4 - (4-pyridinyl) -2.pyrimidinamine The procedure of Example 263 was repeated using N- (4-methoxyphenyl )-4-( 4-pyridinyl )-2-pyriraid.inamine, giving 510 mg of the desired product as yellow crystals, mp 124-126°C.
Example 265 N-12-(Diethylamino) ethyl ]-4-( 14-( 3-pyridinyl )-2pyrimidiny 13 amino ] benzamide A 1.55 ml portion of diethyIethylenediamine was added to a solution of 0.01 mole of 4-((4-(3-pyridinyl)-2pyr imi dinyl J ami no J benzoic acid chloride in 50 ml of 1,2,dimethoxyethane. A 10 ml portion of triethylamine was *z added and the mixture was stirred for 2 hours. The solid was collected, washed with water and recrystallized from absolute ethanol, giving 1.22 g of the desired product, mp 148-150°C. -80Example 266 N-Methyl-4-((4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide A 5.85 g portion of 4-((4-(3-pyridinyl)-2-pyrimidinyllamino]benzoic acid; in 30 ml of thionyl chloride was refluxed on a steam bath for one hour, then evaporated to dryness. The residue was boiled with dimethoxyethane, then cooled and the solid recovered and washed with ether, giving 6.90 g of 4-((4-(3-pyridinyl)-2-pyrimidinylJamino]benzoic acid chloride.
A 6.03 g portion of the above acid chloride was suspended in 25 ml of ethanol and 10 ml of 25% aqueous methyl amine was added. The resulting solid was collected, taken up in hot 2-methoxyethanol, cooled and the solid collected, giving 3.35 g of the desired product, mp 254-257°C.
Example 267 4-([4-(3-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid To a solution of 19.89 g of 4-((4-(3-pyridinyl)2-pyrimidinyl]amino]benzoic acid, ethyl ester in 200 ml of 3A ethanol was added 12.5 ml of 10N sodium hydroxide.
This mixture was refluxed on a steam bath for 3 hours and then allowed to evaporate. The residue was taken up in water and treated with 10.4 ml of concentrated hydrochloric acid. The resulting solid was collected and dried, giving 18.11 g of the desired product, mp 311-317°C.
Example.2 68 (4-([4-(4-Pyridinyl)-2-pyrimidinylJamino]phenoxy]acetic acid An 800 mg portion of (4-((4-(4-pyridinyl)-2pyrimidinyl]amino]phenoxy]acetic acid, ethyl ester was dissolved in 100 ml of ethanol and 10.7 ml of IN sodium hydroxide was added. The mixture was stirred for 2 hours, the solvent removed and the residue dissolved in 5 ml of water. The pH was adjusted to 7.0 with IN hydrochloric acid and the solid collected, washed with water and dried.j -81The solid was recrystallized from dimethylformamideethanol, giving 600 mg of the desired product as yellow crystals, mp 308-310°C.
Example 269 4-(2-((4-Methoxyphenyl)amino]-4-pyrimidinyl]-lmethylpyridinium iodide A 2.0 g portion of N-(4-methoxyphenyl )-4-(4pyridinyl-2-pyrimidinamine was dissolved in 550 ml of absolute ethanol and filtered. To this was added 10 ml of iodomethane. The reaction was heated on a steam bath for 4 hours. Another 10 al of iodomethane was added and refluxing was continued overnight. The mixture was cooled, the solid collected, washed with ethanol and dried, giving 2.2 g of the desired product as purple crystals, mp 282284°C.
Example 270 4-([4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol A 25.0 g portion of N-(4-methoxyphenyl)-4-(3pyridinyl)-2-pyrimidinamine was dissolved in 200 ml of 48% hydrobromic acid and stirred overnight under an argon atmosphere. The mixture was then heated on a steam bath for 7 hours, cooled overnight and evaporated at 60 °C. The residue was basified with 200 ml of saturated potassium bicarbonate solution and stirred for 1.5 hours. The solid was collected, washed with water, dried find recrystallized from hot absolute ethanol, giving 19.1 g of the desired product, mp 223-225°C.
Example 271 4-((4-(4-Pyridinyl)-2-pyrimidinyl ] The procedure of Example 27.0 was repeated using N—(4—methoxyphenyl,-4-(4-pyridinylH2-pyrimidinamine, giving 3.0 g of the desired product as yellow crystals, mp 268-270°c. j -82Example 272 N-{ 4-(2-Propenyloxy)phenyl]-4-(3-pyridinyl)-2pyrimidinamine A 2.73 g portion of dry 4-((4-(3-pyridinyl,-2pyrimidinyllamino]phenol was dissolved in 50 ml of dry dimethylformamide. A 528 mg portion of sodium hydride (50% in oil) was added, the reaction was sealed and stirred for 45 minutes. A solution of 1.33 g of allyl bromide in 10 ml of dimethylformamide was added, the sealed mixture was stirred overnight and then evaporated at 80°C. The residue was partitioned between water and chloroform. The organic phase was separated, dried and filtered. The filtrate was evaporated and the residue crystallized from chloroform-hexane, giving 1.7 g of the desired product as yellow crystals, mp 105-108®C.
Example 273 N-(4-Ethylphenyl )-4-(4-pyridinyl)-2-pyrimidinamine, pyridine-1-oxide A mixture of 2.76 g of N-(4-ethylphenyl,-4-(4pyridiny 1, -2-pyrimidinamine and 3.45 g of m-chloroperbenzoic acid in 100 ml of dichloromethane was stirred at room temperature for 20 hours. The mixture was washed three times with an aqueous saturated solution of sodium bicarbonate and a small amount of saturated saline. The organic layer was dried over magnesium sulfate,, filtered through diatomaceous earth, then evaporated in vacuo to give a gelatenous solid. The solid was slurried with 50 ml of dichloromethane and filtered. The solid was washed with a small amount of dichloromethane and air dried to give 500 mg of the product. Recrystallization from absolute methanol gave 460 mg of the desired product, mp 223-225°C. -83Example 2 74 N-Phenyl-4-( 4-pyridinyl)-2-pyrimidinamine, di hydrochloride A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2pyrimidinamine was dissolved in 70 ml of dichloromethane with warming. The solution was cooled to room temperature, then hydrogen chloride gas was bubbled in to give a brick red precipitate. The mixture became very thick and more dichloromethane was added. The precipitate was collected, air dried, then dried in vacuo and gave 2.63 g of the desired product as red-orange crystals, mp 259-262°C.
Example 275 . N-l 4- (4-Pyridinyl )-2-pyrimidinyl ]-l, 4-benzenediamine, hydrochloride A 2.85 g amount of N-[ 4-((4-(4-pyridinyl)-2pyrimidinyl]amino]pheny 1 ]acetamide was added to a mixture of 10 ml of concentrated hydrochloric acid and 10 ml of water. The reaction mixture was heated at reflux for 90 minutes, then evaporated in vacuo to obtain a solid. The solid was recrystallized from 3A ethanol/water and gave 2.31 g of the desired product as a yellow crystalline solid, mp 292-295°C.
Additional hydrochloride salts listed in Examples 276 to 287 in Table V were obtained from the corresponding base compound by following procedures similar to those described in Examples 274 and 275 and employing various other solvents such as isopropyl alcohol, ethanol, ether and the like. -84Ex 276 277 278 279 280 281 282 283 284 285 286 287 TABLE V Compound MP°C 4-(3-Pyridiny1)-N-(3-trifluoromethyl )pheny 1 ] pyrimidinamine, hydrochloride N, N-Dimethyl-N* -(4-( 3-pyridinyl) -2-pyr imidinyl ]-1,4-benzenediamine, trihydrochloride N-14 - (2- (Die thylamino) e thoxy ] pheny 1 ] -4(3-pyridinyl) -2-pyrimidinamine, hydrochloride N, N-Dimethyl-N* -(4-( 2-pyridinyl) -2-( pyr imidinyl ) ]-1, 3-benzenediamine, dihydrochloride N,N-Dimethyl-N* -(4-(2-pyridinyl )-2-pyr imidinyl ]-1,3-benzenediamine, trihydrochloride N, N-Dimethyl-N *-14-(4-pyridinyl)-2-pyr imidinyl ] -1,3 -benzenediamine , dihydrochloride N,N-Dimethyl-N* -(4-( 2-pyridinyl )-2-pyr imidinyl ] -1,4-benzenediamine, dihydrochloride N, N-D ime thy-N · - (4- (4-pyridinyl) -2-pyrimidiny 1 ] -1,4-benzenediamine, trihydrochloride N-14- (1-Aminoethyl) phenyl 1-4- (3-pyridinyl) 2-pyrimidinamine, trihydrochloride H- (3- (ΙΗ-Imidazol-l-yl) phenyl] -4- (2-pyri- 1232.5dinyl)-2-pyrimidinamine, hydrochloride vH-(3-(ΙΗ-Imidazol-l-yl)phenyl]-4-(4-pyridinyl)-2-pyrimidinamine, hydrochloride 4-(2-Furanyl)-N-(3-(4-methyl-l-piperazinyl) phenyl ] -2-pyrimidinamine, hydrochloride 220-223 239-245 115-150 (dec) 204-213 202-205 178-184 229-234 232-235 234 259-266 259-263 Example 288 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, sulfate A 2.48 g amount of N-pheny1-4-(4-pyridinyl)-2pyr imidi nami ne was dissolved in 120 ml of absolute ethanol with heating, then a solution of 1.02 g of concentrated sulfuric acid in 25 ml of ethanol was added dropwise with stirring. The mixture turned orange then a yellow precipitate formed. The mixture was chilled, the preciptate -85was collected, by filtration, washed with cold ethanol then with ether, and air dried to give 2.73 g of yelloworange crystals.
The preceding compound was dissolved in a small amount of water, then a saturated aqueous solution of sodium bicarbonate was added to pH 8.0 to yield a light yellow precipitate. The precipitate was collected, washed with water and dried in vacuo. A 2.25 g portion this material was recrystallized from about 200 ml of absolute methanol in the cold. The product was collected, washed with absolute ethanol and dried in vacuo to give 1.75 g of the desired product as orange cyrstals, mp 233-235°C.
Additional sulfate salts which were prepared from the corresponding base compound in the manner described hereinabove are listed as Examples 289 to 300 in Table VI.
TABLE VI Ex Compound J MP°C 289 4-(2-Pyridinyl)-N-I3-trifluoromethyl)phenyl]-2-pyrimidinamine, sulfate 208-211 290 N-(3-Methylpheny1)-4-(2-thienyl)-2-pyrimidinamine, sulfate 207.5- 210 291 4-(2-Furanyl)-N-(3-methylphenyl)-2-pyrimidinamine sulfate 187-193 292 4-(4-Pyridinyl)-N-(3-(trifluoromethyl)phenyl ) ] -2-pyrimidinamine, sulfate 250-253 293 N-(4-Methoxyphenyl)-4-(3-pyridiny1)-2pyrimidinamine, sulfate 103-123 294 N-Phenyl-4-(3-pyridinyl)-2-pyrimidinamine, sulfate 167-187 29i 4-(3-Pyridinyl)-N-(3-trifluoromethyl)phenyl ]-2-pyrimidinamine, sulfate 196-199 1 -86TABLE VI (continued) |ex | Compound MP°C 296 N-(3,5-Dimethylphenyl)-(4-(3-pyridinyl)-2pyrimidinamine, sulfate 209-214 297 N-(3,5-Dimethylpheny1)-4-(2-pyridinyl)-2pyrimidinamine, sulfate 216-218 298 N-(3,5-Dimethylpheny1)-4 -methyl-6-(5-methy12-thienyl)-2-pyrimidinamine, sulfate 232-234 299 4-( 2-Furanyl)-5-me thy 1-N-phenyl-2-pyr imidinamine, sulfate 140-144 | 300 1 N,N-Dimethyl-N*-(4-(4-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine, sulfate 204-211 Example 301 N-Phenyl-4-(4-pyridinyl )-2-pyrimidinamine, phosphate A 2.0 g amount of N-phenyl-4-(4-pyridinyl )-2pyrimidinamine was dissolved in 100 ml of ethanol with heating. The solution was allowed to cool to room temperature, then a solution of 2.07 g of phosphoric acid in 25 ml of ethanol was added with stirring. The mixture was chilled for several hours, then the precipitate which formed was collected by filtration, washed twice with cold ethanol and dried in vacuo for 16 hours to give 3.43 g of the desired product as orange crystals, mp 210.5-212.S^c.
Additional phosphate salts which were prepared from the corresponding base compound in the manner described hereinabove are listed as Examples 302 to 305 in Table VII. -87TABLE VII Ex Compound MP°C 302 N-(3,5-Dimethylphenyl,-4-(3-pyridinyl)-2pyrimidinamine, phosphate 190-192 303 N-(4-Methoxypheny1)-4-(3-pyridinyl,-2pyrimidinamine, phosphate 185-188 304 N-Phenyl-4-(3-pyridinyl)-2-pyrimidinamine phosphate 176-179 305 N— (3,5-Dimethylphenyl)-4-(2-pyridinyl)-2pyrimidinamine, phosphate 199-202 Example 306 N-Phenyl-4- (4-pyridinyl) -2-pyrimidinamine, (2)-2-butenedioate(1:1) A mixture of 4.97 g of N-pheny1-4-(4-pyridiny 1)2-pyrimidinamine and 2.55 g of maleic acid was dissolved in hot 2-methoxyethanol. Cooling gave 4.15 g of the desired product as an orange crystalline solid, mp 211214°C.
Example 307 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, dinitrate A 2.0 g amount of N-pheny1-4-(4-pyridinyl,-2pyrimidinamine was dissolved in 100 ml of ethanol with heating. The solution was allowed to cool to room temperature, then a solution of 1.5 ml of concentrated nitric acid in 25 ml of ethanol was added with stirring to give a red-orange precipitate. The mixture was allowed to stand 30 minutes at room temperature, then was chilled for several hours. The solid was collected, washed with cold absolute ethanol and air dried to give 2.80 g of the desired product as red—orange crystals, mp 167—169°C (dec.). -88Example 308 N-Pheny1-4-(4-pyridinyl,-2-pyrimidinamine, compound with 2-hydroxy-l,2,3propanetricarboxyla te (2:1) A mixture of 4.97 g of N-pheny1-4-(4-pyridinyl)2-pyrimidinamine and 4.62 g of citric acid was dissolved in hot absolute ethanol. Cooling gave 6.14 g of the product of the example as a yellow cystalline solid, mp 155—157°CExample 309 0xo(phenyl(4-(4-pyridinv1)- 2-pyrimidinyl lamino]acetic acid, ethyl ester A 4.08 g portion of 2-phenylamino-4-(4-pyridinyl) pyrimidine was dissolved in 20 ml of dimethylformamide. A 5 g portion of 50% sodium hydride in oil was added using 10 ml of dimethylformamide as a wash. When bubbling ceased, a solution of-2.23 ml of ethyl oxalyl chloride in 10 ml of dimethylformamide was added dropwise. Chloroform and aqueous 10% potassium bicarbonate were added. The organic layer was separated, dried, filtered and evaporated giving the desired product.
Example 310 K- ( 4- ( 2-Pyridinyl) -2-pyrimidinyl ] -1,4benzenediamine. dihvdrochloride A 12.86 g portion of fi-(4-([4-(2-pyridinyl,-2pyrimidinyl] amino]phenyl]acetamide in a mixture of 40 ml of vater and 40 ml of concentrated hydrochloric acid was refluxed for 30 minutes and then cooled. The solid was collected and dried, giving 10.84 g of the desired product, mp 285—288°C.
Following the procedure of this Example, and using as starting materials the products of the indicated examples, the products of Examples 311-322 in Table VIII were derived. -895 TABLE VIII Ex. Starting Material Product MP°C 10 311 Ex. 185 fi-Methyl-N· -(4- (3-pyridiny 1) -2pyrimidinyl ]-1,4-benzenediamine 164—166 312- Ex. 187 fi-Methyl-N'-(4-(2-pyridinyl)-2pyrimidinyl ] -1,4-benzenediamine 110-112 15 313 Ex. 218 fi- ( 4- (3-Pyridiny1)-2-pyrimidinyl]1,3-benzenediamine, dihydrocbloride 279-284 314 Ex. 217 fi-[4-(4-Pyridinyl)-2-pyrimidinyl]1,3-benzenediamine 199-202 20 315 Ex. 221 2-Methyl-N-(4-(4-pyridinyl)-2pyrimidinyl ] -1,4-benzenediamine, dihydrochloride 297-304 316 Ex. 219 fi-(4-(2-Pyridinyl)-2-pyrimidinyl]1,3-benzenediamine 153-156 317 Ex. 182 fi- (3-(1-Aminoeethyl,phenyl]-4-(3pyridinyl)-2-pyrimidinamine 230(dec.) J i 25 318 Ex. 222 fi-(4-(5-Methyl-2-thienyl) -2-pyrimidinyl)-1,4-benzenediamine, dihydrochloride 284-287 319 Ex. 228 fi-[4-(2-Furanyl)-2-pyrimidinyl]-l# 4benzenediamine, dihydrochloride 261-266 30 320 Ex. 226 2-Methyl-N-(4-(3-pyridinyl)-2-pyrimidinyl)-1,4-benzenediamine 176-178 321 Ex. 230 2-Methyl-N-(4-(2-pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine 196-198 322 Ex. 191 fi- (4- (4-Pyridinyl) -2-pyrimidinyl J 1,4-benzenediamine 192-193.5 -90Rxample 3?3 2-Γ1-Γ4-Γ Γ4-(3-Pvridinvl)-2-pyrimidinyΠβτηΐηο 1phenvl)ethvlidene T hvdraz inecarboxamide A 2.9 g portion of l-[3-([4-(3-pyridinyl)-2pyrimidinyl]amino]phenylJethanone was mixed with 1.23 g of semicarbazide hydrochloride in 200 ml of absolute ethanol and 1.10 ml of ION sodium hydroxide was added. This mixture was refluxed overnight, then cooled to room temperature and the solid collected and washed with ethanol, water and ethanol. The solid was recrystallized from dimethylsulfoxide/ethanol, giving 2.9 g of the desired product, mp 256-258°C.
Ryample 374 N-[4-[2-[bis (1-Methy1ethyl) amino]ethoxy]phenyl]4-(3-pyridinyl)-2-pvrimidinamine A 2.64 g portion of 4-[[4-(3-pyridinyl)-2-pyrini dinyl]amino]phenol was dissolved in 60 ml of dimethylforma mide by warming on a steam bath and then cooled. A 2.0 g portion of diisopropylaminoethyl chloride hydrochloride was added and dissolved vith stirring. A 20 ml portion of 5N sodium hydroxide was added dropwise over 5 minutes, then 5 ml of water was added and the mixture was stirred for 20 hours. The mixture was then heated on a steam bath for 30 minutes, allowed to stand 48 hours and then evaporated. The residual gum was purified by flash dry column chromatography on silica gel eluting fractions 1-3 with methanol and fractions 4-6 with 1% methanol in chloroform. Fractions 4-6 were combined and evaporated, giving 500 mg of the desired product.
Example 325 a-Methvl-4-Γ f4-(3-ovridinvl)-2-ovrimidinvl1amino)benzenemethanol A 1.45 g portion of l-(3-((4-(3-pyridinyl)-2pyrimidinyl]amino]phenyl]ethanone was dissolved with stirring in 220 ml of ethanol. A 125 mg portion of sodium borohydride was added and stirring continued for 3 hours.
A 63 mg portion of sodium borohydride was added and -91stirring continued overnight. A 2 ml portion of glacial acetic acid was added and the mixture evaporated. The solid was triturated with water, dried and recrystallized from 30 ml of ethanol giving 710 mg of the desired product, mp 145-147°C.
Example 326 {£-(1-(3-((4-(3 -Pyridinyl) -2 -pyr imidiny 1 Jamino ] phenvl1ethvl1formamide A mixture of 2.9 g of l-(3-[(4-(3-pyridinyl)-2pyrimidiny 1J amino J phenyl J ethanone, 40 ml of formamide and 13 ml of concentrated formic acid was refluxed for 15 hours, then cooled and evaporated. The residue was partitioned between unsaturated aqueous potassium bicarbonate and chloroform. The organic phase was separated, dried, filtered and evaporated. The residue was chormatographed on silica gel, eluting 125 ml fractions, fractions 1-4 with chloroform and fractions 5-7 with 2% methanol in chloroform. Fractions 5-7 were combined and evaporated, giving 1.25 g of the desired product as a yellow foam.
Example 327 2-Γ f 4-(3-Pvridinvl)-2-pyrimidinvn amino 1 phenol A mixture of 35 g of {£-(2-methoxyphenyl)-4-(3pyr idinyl)-2-pyrimidinamine in 200 ml of 47% aqueous hydrobromic acid was refluxed for 7 hours and then evaporated. The residue was mixed with saturated aqueous potassium bicarbonate and allowed to stand overnight, then filtered. The filtrate was concentrated, giving 3.5 g of the desired compound, mp 166-169°C. -92Example 328 N- [ 3- (ΙΗ-Imidazol-l-yl) phenyl ] -4- (2-pyridinyl) -2pyrimidinamine A solution of 250 ml of 2-acetylpyridine and 500 ml of £,N-dimethy1formamide dimethyl acetal was heated on a steam bath for 6 hours. After concentrating the reaction solution under vacuum, 1 liter of hexane vas added to the part crystalline residue. The product was collected as small crystalline particles which were washed with an additional liter of hexane. Air drying was followed by drying at 45°C under vacuum, leaving 350.7 g of 3-dimethylamino-1- (2-pyridinyl) -2-propen-l—one.
A mixture of 289.0 g of imidazole, 292 g of potassium carbonate, 3 liters of dimethyl sulfoxide, and 300.0 g of l-fluoro-3-nitrobenzene was stirred and heated for 25.5 hours between 105-110°C. Then the reaction vas poured into 6 libers of water and cooled in the refrigerator over the weekend. The crystalline product vas collected and washed with 1 liter of water. Air drying gave 357.6 g of solid. The solid was taken up in 2.4 liters of ethyl acetate and the hot solution passed through hydrous magnesium silicate. After boiling the filtrate down to 1.5 liters, it was cooled to give a precipitate which was collected and washed with 200 ml of ethylacetate, to leave 151.7 g of off-white crystals. After evaporating the mother liquor to dryness,the residue vas recrystallized from 350 ml of ethyl acetate to give 59.7 g more product. The mother liquor from the second fraction was evaporated and the residual material recrystallized twice from ethyl acetate to give 30.9 g more product. Total product, 242.3 g of 1-(3-nitrophenyl)-1H-imidazole.
In a Parr hydrogenation bottle was placed 75.00 g of l-(3-nitrophenyl)-1H-imidazole, 0.70 g platinum oxide, and 250 ml of ethanol. Shaking of this mixture in a Parr -93hydrogenation apparatus was continued until no more hydrogen was taken up. This process was repeated with 76.33 g of the imidazole, 1.0 g of platinum oxide and 250 ml of ethanol and again vith 90.4 g of the imidazole, 1.0 g of platinum oxide and 240 ml of ethanol, until a total of 241.63 g had been reduced. For each batch the catalyst was filtered off and the solvent was removed under vacuum; and then the residues were combined to give 207.2 g of gray crystalline amine. Next the amine was recrystallized from 530 ml of 2-propanol. After collecting the product, it was washed with 200 ml of 2-propanol, and dried, under vacuum, to give 156.4 g of 3-(IH- imidazol-1-yl) benz amine.
A solution of 43.3 g of hydrogen chloride in 290 ml of ethanol was added to 189.0 g of 3-(lH-imidazol-ly 1)benzamine in a 2 liter Erlenmeyer flask. Then 104.7 g of cyanamid was added. The mixture was cautiously warmed in a water bath to an internal temperature of 83°C over 25 minutes. When no exotherm had been noted, the flask was placed inside the steam hath and heated for 2 hours. A final temperature of 97°C was achieved. The resulting brown syrup which was (3-(IH-imidazol-1-yl) phenyl]guanidine, monohydrochlaride, was used in the next reaction without further purification.
A mixture of 164 g of potassium carbonate, 209.1 g of 3-dimethylamino-l-(2-pyridyl) -2-propen— l-one, 1.187 mole of crude (3-(ΙΗ-imidazol-l-yl)phenyl]guanidine monohydrochloride, and 1 liter of methoxy ethanol was stirred and heated under very gentle reflux. A dry-ice condenser filled with water was used to prevent plugging by the dimethylammonium carbonate which is given off by the reaction. The reaction was stopped after 26.5 hours and permitted to stand overnight. A heavy precipitate had formed which was collected as A and washed vith 100 ml of ether. The filtrate was concentrated under vacuum as B. Both A and B were triturated with 1.5 liters of water.
Then A was washed with 300-400 ml of ethanol, followed by 100 ml of ether to leave, on drying, 172.9 g of gray solid, -94mp 200-202°C. Recrystallization of B from 150 ml of 2-propanol gave a black solid, C. Next, a classical fractional recrystallization was carried out using methoxyethanol as the solvent. In the final stages, a large amount of charcoal was added to remove color. In this fashion two main fractions were obtained D, 79.0 g of yellow crystals, mp 204.5-205.5°C, and E, 18.05 g of yellow crystals, mp 204-204.5°C. The yield of D plus E was 26% of the desired product.
EXAMPLE 329 1-(2-Chloroethoxy)-3-nitrobenzene A mixture of 6.96g. of m - nitrophenol, 100 ml. of 2-butanone, 6.9 g. of potassium carbonate, and 11.74 g. of 2 chloroethyl-tosylate was stirred and heated under reflux for 24 hours. After cooling to room temperature, the salts were filtered off and the filtrate concentrated under vacuum. The residue crystallized on seeding and was recrystallized from carbon tetrachloride to give 8.3 g. of product, m.p. 54.5° - 57° C.
EXAMPLE 330 l-[2-(3-Nitrophenoxy)ethyl]-IH-imidazole After dissolving 3.74 g. of imidazole in 60 ml. of dry Ν,Ν-dimethylformamide, 1.78 g. of 50¾ sodium hydride in oil was added. When the effervescence had stopped (circa 1 hr.),7.35 g. of 1-(2-chloroethoxy)-3-nitrobenzene was added. After stirring overnight, the reaction was concentrated under vacuum. Water was added to the residue and the product was extracted into chloroform. The product was extracted out of the chloroform layer with dilute hydrochloric acid. Next, the aqueous acid layer was neutralized with potassium carbonate and the oily product extracted into chloroform. Upon drying the chloroform extract with sodium sulfate, it was concentrated under vacuum to an oil which -95crystallized on standing. Recrystallization from isopropyl acetate gave 6.12 g. of product as the monohydrate, m.p. 52.5°-55.5° C.
EXAMPLE 331 3-[2-(lH-lmidazol-l-yl)ethoxy]benzamine Using a Parr hydrogenator, 5.00 g. of 1-(2-(3nitrophenoxy)ethyl]-ΙΗ-imidozole in 100 ml. of ethanol and 0.2 g. of platinum oxide was hydrogenated until the hydrogen uptake stopped. The catalyst was filtered off and the filtrate concentrated under vacuum. Several recrystallizations from isopropyl acetate gave 2.8 g. of amine, m.p. 74°-76.5° C.
EXAMPLE 332 [3-(2-(1H-Imidazol-1-yl)ethoxylphenyl]-guanidine Ώihydrochloride To a solution of 1.7 g. of hydrogen chloride in 50 ml. of ethanol was added 4.70 g. of 3-[2-(lH-imidazol-lyl)ethoxy]benzamine in 10 ml. of ethanol. After concentration under vacuum a foam was obtained which gradually crystallized. Next 1.95 g. of cyanamid and 20 ml. of ethanol were added and the mixture heated cautiously, first in a water bath, then directly in a steam bath for a total of 5 hours. A light brown'oily guanidine resulted, which was used without purification.
EXAMPLE 333 3-(2-(4-Morpholinyl)ethoxy]-benzenamine N-[2-Chloroethyl)morpholine hydrochloride, 80 g., was partitioned between 5N sodium hydroxide and methylene chloride. After drying the organic layer over magnesium sulfate, the solvent was removed under reduced pressure to leave 65 g. of free amine.
To 36.01 g. of m-aminophenol dissolved in 325 ml. of N,N-dimethylformamide, 16.3 g. of 50X sodium hydride in oil was added. The reaction was stirred for 1 hour, until the effervescence stopped; then 57 g- of N-(2-chloroethyl) -96morpholine, from above, was added. After stirring overnight, the mixture was heated on a steam bath for 1/2 hr., then concentrated under vacuum. The residue was taken up in 300 ml.of 2N hydrochloric acid and washed twice with ether. After basifying with 10N sodium hydroxide, the product was extracted into ether, dried (magnesium sulfate), filtered through hydrous magnesium silicate and evaporated to a brown oil. Distillation gave 34.0 g. of a golden oil, b.p. 165°180*3 C./0.45mm.
EXAMPLE 334 [3-(2-(4-Morpholinyl)ethoxy]phenyl] guanidine monobydrochlor ide Prepared from 3-i2-(4-morpholinyl)ethoxy l~benza-mine by the method of Example 332 EXAMPLE 335 1-(Bromoacetyl)-4-methylpiperazine monohydrochloride A solution of 10.0 g. of 1-methyepiperazine in 150 ml of chloroform was cooled in a water bath while 17.3 g. of bromoacetyl chloride in 150 ml. of chloroform was added dropwise, with stirring, over 1/2 hour. A calcium chloride tube protected the reaction from moisture. After stirring overnight, the precipitate was collected and washed witn cmoroform. Tne crude product was dried under vacuum at 50° and used as such.
EXAMPLE 336 1-[(4-Aminophenoxy)acetyl]-4-methylpiperazine Prepared from p-aminophenol and 1-(bromoacetyl)-4methylpiperazine by the method of Example 333 to give a product of m.p. 7l°-73° C.
EXAMPLE 337 l-[(4-((Aminoiminomethyl)amino]phenoxy]acetyl]-4methylpiperazine Dihydrochloride Prepared from 1-((4-aminophenoxy)acetyl]-4methylpiperazine by the method of Example 332. -97Ex. 338 339 TABLE IX Acryloyl Source Ex.
Ex. 340 Ex. 341 Ex. 342 Ex.
Phenylguanldine precurser [3-(2-(lH-Imidazol -l-yl)-echoxy]phenylIguanidine dihydrochloride (3-(2-(4-morpho1inyl)-ethoxy]phenylIguanidine monohydrochloride (3-(2-(4-morpholinyOethoxy]phenylIguanidine monohydrochloride (3-(2-(4-morpholinyl)ethoxy]phenylIguanidine monohydrochloride 1-(14-((Aminoiminomethyl )amino]phenoxy J acetyl]-4methyl piperazine d ihydrochlor ide Product Mp°C.
N-[3-(2-(lH- 149-Imidazol-l-yl)- 151.5 ethoxy]phenyl-4-(2-pyridinyl) -2-pyrimidinamine N-(3-(2-(4-mor- 179pholinyl)- 181 ethoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine N- (3-12-(4-morpholinyl)ethoxy] phenyl]-4-(2thienyl)-2-pyrimidinamine 4-(2-furanyl)-Nl3-(2-(4-morpho1inyl)ethoxy]phenyl]-2-pyrimidinamine 134136 8890 l-Methyl-4-([4- 173-(2-thienyl)-2- 175 pyrimidinylj-aminophenoxy]acetyl piperazine -98TABLE IX (continued) Ex. Acryloyl Source Phenylguanidine precurser Product Mp°C. 343 Ex. 24 (4-chlorophenyl) guanidine carbonate N-(4-chlorophenyl) -4-(2-thieny1)-2pyrimidinamine 185- , 186 344 Ex. 26 [2-[bis(1-methylethyl)amino[ethoxy [guanidine hydrochloride N-[2-[2-[bis(l-methylethyl) aminoJethoxy] phenyl]-4-(3-pyridinyl)-2-pyrimidinamine 54- 57 The disease diabetes meliitus is characterized by metabolic defects in the production and utilization of glucose which results in the failure to maintain appropriate blood sugar levels. The result of this defect is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes meliitus are now recognized. Type I diabetes, or insulin-dependent diabetes, is a result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulinindependent diabetes, often occurs in the face of normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin The compounds of the present invention and the pharmacologically active acid-addition salts thereof, effectively lower blood glucose levels when administered orally to genetic strains of hyperglycemic mice which are animal models -99of type II diabetes. The exact mechanism hy which they act is not known and the invention should not be construed as limited to any particular mechanism of action. As effective hypoglycemic agents, these compounds are useful for the treatment of hyperglycemia in type II diabetes.
The compounds of this invention were tested for hypoglycemic activity according to the following procedure.
Obese mice (C57 B1/6J (ob/ob)], their lean littermates (ob/+ or +/+) and diabetic mice [C57 Bl/Ks (db/db)] and their non-diabetic littermates (db/+ or +/+) were obtained from Jackson Laboratories, Bar Harbor, Maine. Obese mice were 3 weeks of age and diabetic mice were 9 weeks of age at the start of the test.
The test compounds were dissolved in methanol, mixed with powdered food Purina rodent chow on a weight of compound to weight of chow basis and thoroughly dried.
Groups of 4 control mice received vehicle (methanol) treated chow.
Groups of 4 test mice were fed ad libitum for one month and food consumption was measured daily (on week days) by weighing the food bins before and after the addition of fresh chow. Thus a 40 g mouse fed the test compound at a concentration of 0.02% of the diet would receive a dose of 20 mg/kg/day if it ate 4 g of chow per day.
Blood samples were collected before the first treatment and once at the end of each week of treatment by retro-orbital puncture using the end of each week of treatment by retro-orbital puncture using heparinized capillary tubes. Plasma was separated by centrifugation in a Beckman microfuge for 5 minutes. Plasma glucose concentrations were determined with the Beckman Glucose Analyzer which uses a glucose oxidase method.
The results of this test on representative compounds of this invention appear in Table X.
TABLE X Effect of Test Compounds on Blood Glucose COMPOUND Type of Mice Dose % (W/W) Blood Glucose Levels in mg/lOOml 0 Days 14 21 28 5 7 N-(4-methylphenyl)-4-(4pyridinyl) -2-pyrimidiri'«nine ob/ob ob/ob ob/ob 0.1 0.1 0.025 219 210 209 137 118 223 80 166 N- (4rQilorophenyl)-4- (2thlenyl)-2-pyrimidinanine ob/ob ob/ob 0.1 0.025 212 220 160 148 134 N-(4-ethylphenyl) -4-(4pyridinyl)-2-pyrimidinamine ob/ob ob/ob 0.1 0.1 216 223 181 164 4-(2-furanyl)-N-phenyl-2pyrimidinamine ob/ob 0.1 214 166 -001Table X Cont’d.
COMPOUND Type of Mice Dose % (W/W) Blood Glucose Levels in mq/lOOml 0 I 5 )ays 7 14 21 28 135 188 162 207 270 199 ! N- (4-(1,1-Dimethylethyl) phenyl]-4- (4»pyridinyl)-2py r imidi retrain e * ob/ob ob/ob ob/ob ob/ob ob/ob ob/ob ob/ob db/db db/db db/db ί 0.1 0.1 0.1 0.1 0.1 0.05 0.01 0.1 0.05 0.01 208 214 218 229 225 214 214 426 429 431 114 169 124 110 175 155 120 139 163 390 314 335 116 143 138 174 293 407 131 180 181 281 250 400 fl-[4-(Dimethylamino) phenvl ] -4-(4-pyridinyl)-2pyrimidinamine ob/ob ob/ob 0.1 0.1 240 230 130 147 - | 1 N-(4-(3-(Dimethylamino)propc phenyl)-4-(3-pyridinyl) -2-pyrimidinamine >xyl ob/ob 0.1 215 234 N-[4- (2- (jjiethylamino)ethoxy phenyl]-4-(3-pyridinyl)-2pyrimidinamine ob/ob 0.1 220 191 -ιοίTable X Cont’d COMPOUND Type of Mice Dose % (W/W) Blood Glucose Levels in mq/lOOml 28 0 -Pays14 21 5 7 Ν'- (4-(2-feenzofurnayl)-2- ob/ob 0.1 229 153 pyriLroidiriyl) -M,'N-dimethyl - ob/ob 0.1 202 147 L,4-benzenediamrne ob/ob 0.1 223 144 N-14-(2-(Dimethylam- ob/ob 0.1 210 151 167 Γηο)ethoxy] phenyl] -4- ob/ob 0.1 228 144 (4-pyridinyl)-2- ob/ob 0.1 225 134 pyrimidinamine ob/ob 0.1 232 148 128 155 140 ob/ob 0.05 230 158 198 196 163 ob/ob 0.01 236 163 252 175 177 db/db 0.1 369 410 403 328 222 db/db 0.05 400 277 404 329 250 db/db 0.01 360 393 321 494 336 N-ί 4- (lH-.Bnidazol-l- db/db 0.1 424 397 233 "yi)phenyi] 4 - (4-pyriainyl)-2-pyrimidin- ob/ob 0.1 219 123 amine ob/ob 0.025 210 200 148 ob/ob 0.1 211 105 140 ob/ob 0.1 222 119 132 ). ' ob/ob 0.01 219 ' 158 159 ob/ob 0.075 222 157 175 N.N-DLethyl-N1- (4- ob/ob 0.1 223 138 T3-pyridinyir_2-pyrim- ob/ob 0.1 210 163 idinyl]-l,4-benzene- ob/ob 0.1 216 153 diamine- - 1 -102Table χ Cont'd COMPOUND Type of Mice Dose % (W/W) Blood Glucose Levels in mg/lOOml 28 0 Days 7 14 21 N- (4-(lH-Imidazol- ob/ob 0.1 225 128 Γ-y1,phenyi 1-4-(3- ob/ob 0.025 208 159 171 pyridinyl)-2-pyrimidinamine ob/ob 0.1 210 127 131 N- (4-(1H-Imidazol- ob/ob 0.1 217 171 Γ-y1, phenyl1-4-(2- ob/ob 0.1 223 167 pyridinyl)-2-pyrimidinamine ob/ob 0.1 234 141 4-(2-Furany1)-R-[4- ob/ob 0.1 227 137 (lH-imidazol-l-yl) ob/ob 0.025 215 164 244 phenyl]-2-pyrimidinamine ob/ob 0.1 214 140 160 N- (4-(1H-Imidazol- ob/ob 0.1 221 109 116 1-yl) phenyl]-4-(2- ob/ob 0.025 221 147 171 thienyl)-2-pyrimid- ob/ob 0.01 217 212 161 inamine ob/ob 0.1 224 125 ob/ob 0.1 203 131 ob/ob 0.1 231 126 ob/ob 0.1 218 134 ob/ob 0.025 218 175 185 ob/ob 0.1 220 135 117 db/db 0.1 423 492 349 -103Table X Cont’d COMPOUND Type of Mice Dose & (W/W) Blood Glucose Levels in mg/lOOml Days 0 5 7 14 21 28 4-((4-(3-Pyridinyl)2-pyrimidinyl]amino] benzenesulfonamide ob/ob ob/ob ob/ob ob/ob ob/ob 0.1 0.1 0.1 0.1 0.1 219 240 216 229 228 122 147 185 142 211 N-(3-chlorophdnyl)-4 -(4-pyrindinyl)-2pyrimidinamine ob/ob ob/ob ob/ob ob/ob ob/ob ob/ob 0.1 0.1 0.1 0.1 0.025 0.1 220 237 216 205 210 212 127 163 135 157 1 157 173 135 129 N-(3-Qhlorophenyl) -4-(3-pyridinyl)-2pyrimidinamine ob/ob ob/ob ob/ob 0.1 0.025 0.1 205 221 244 135 205 211 131 138 N-(4-(4-Methyl-lplperazinyl) phenyl] -4 — (3-pyridinyl) -2pyrimidinamine ob/ob 0.1 212 236 N- (3-Chloropheny1) T- (2-pyridinyl)-2pyrimldlnamine ob/ob 0.1 207 204 -104Table X ContJd COMPOUND Type of Mice Dose & (W/W) Blood Glucose Levels in mg/lOOml 28 0 5 pays 7 14 21 4-(2-Furanyl)-N- {4(4-methyl-l-piperazlnyl) phenyl]-2pyrimidinatnine ob/ob ob/ob ob/ob 0.1 0.025 0.1 203 210 229 149 179 163 130 141 4-(2-Furanyl)-N(3-methoxyphenyl) -2-pyrimidinamine ob/ob ob/ob ob/ob ob/ob 0.1 0.1 0.1 0.1 221 239 217 219 132 113 162 209 N-[4-(4-Methyl-lpiperazinyl)phenyl J -4-(2-thienyl)-2pyrimidinamine ob/ob 0.1 203 188 N- (4- (4-MethylΓ-piperazi nvl) phenyl) -4-(2-pyridinyl)-2pyrimidinamine ob/ob 0.1 204 210 -105V Table χ Cont'd Type ' Dose Blood Glucose Levels in mq/lOOml COMPOUND of & -Days- - ........ ...ii ice_(W/W) 0 5 14 21 28 N-(4-(4-HethylΓ-piperazinyl)phenyl] -4-(4-pyridinyl)-2pyrimidinamine ob/ob ob/ob ob/ob db/db ob/ob ob/ob ob/ob ob/ob ob/ob 3b/ob 0.1 0.025 0.01 0.1 0.1 0.1 0.1 0.1 0.025 η. i 204 210 210 406 221 233 226 223 125 131 117 130 118 157 130 273 154 171 124 200 192 140 134 137 178 152 178 178 161 202 147 279 N-(3- (IH-ImidazolΓ-yl)phenyl]-4(3-pyridinyl)-2pyrimidinamine ob/ob 0.1 I 225 173 N-(4-(2-(Diethylamino) ethoxy]phenyl]- 4- (2- thienyl) -2-pyrimidinair ob/ob ob/ob ine 0.1 0.1 228 215 154 137 N- (2-(2- [jBis (,1-methylethyl ) amino]ethoxy] phenyl]-4-(3pyridinyl)-2-pyrimidinami ne... ....... ob/ob 0.1 228 153 -106-107-

Claims (17)

1. A compound selected from the group consisting of those of the formula: wherein Ry is hydrogen, alkyl(C^-C^), -COCO2C2H5 or N,Ndimethylaminoethyi; Rj is mono- or poly-substituted phenyl wherein the substituents are alkyKC^-C^), alkoxy(C^-C^), chloro, bromo, trifluoromethyl, hydroxy, phenyl, amino, monoalkyl(C^-cpamino, dialkyl(C^-C^amino, alkyl(Ci-C^keto, propenyloxy, carboxyl, oxyacetic acid, oxyacetic acid ethyl ester, sulfanilamido, N,N-dialkyl(C^-C 3 )sulfanilamido, N-methylpiperazinyl, piperidinyl, lH-imidazol-1-yl, lH-triazol-l-yl, lH-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or moieties of the formulae: u u K. d 11 ' -CO 2 R, -NH-C-R, -NR-C-R, -0-(CH 2 )n-\ , R yHCHO N-OH N-OCH3 n-N , -CH-CH-j ,-C-CH,, -C-CH-C-NH-(CH 2 )n-\ ϊ«2 S / R /-\ -CH-CH-, -NHCH--C-N. , —N 3 2 S R \_/ \=/S -(CH 2 )m-R 7 , -X-(CH 2 )m-R 7 and -X-CH 2 N-R, wherein R is alkyl(Cj-C^), X is oxygen (-0-) or sulfur (-S-), m is 1-3, n is 2 or 3, Rg is hydrogen, alkyl(C 1 ~C 3 ), alkoxy (C^-cp,chloro, bromo, iodo or trifluoromethyl, R? is IK-108-imidazol-l-yl or morpholino and Rg is alkyl(C*-Cg), phenyl or monosubstituted phenyl wherein the substituents are alkyl (Cj _ Cg), halogen or triiluoromethyl; Rg is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl, 2-furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 2-pyrazinyl, 2-benzofuranyl, 2-(pyridine-N-oxide), 3-(pyridine-N-oxide), 4-(pyridine-N-oxide), IH-indol-2-yl, IH-indol-3-yl, l-methyl-lH-pyrrol-2-yl, 4-quinolinyl, 4-pyri-dinyl methyl iodide, dimethylaminophenyl or N-acetyl-N-methylaminophenyl; is hydrogen or alkyl(Cj-Cg); and is hydrogen or alkyl(C^-Cg); and the pharmacologically acceptable acid-addition salts thereof.
2. The compound according to Claim 1; N-(3-(lH-imidazol-1-yl)phenyl J-4-(4-pyridinyl)-2-pyrimidinamine.
3. The compound according to Claim 1; N-(3-(lH-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2-pyrimidinamine.
4. The compound according to Claim 1; N,N-dimethyl-N’-(4-methyl-«-(4-pyridinyl)-2-pyrimidinyl1-1,4-benzenediamine.
5. The compound according to Claim lj N'-(4— (2-furanyl)-5-methy1-2-pyrimidiny11-N,N-dimethyl-1,4—benzenediamine.
6. The compound according to Claim 1; N-(4—(dimethylamino)phenyl]-4-(4-pyridinyl)-2-pyrimidinamine.
7. The compound according to Claim 1/ 4-(2—furanyl)-N-(3-methylpheny1)-2-pyrimidinamine. g. The compound according to Claim 1/ N,N-dimethyl-N’-14-(4-pyridinyl,-2-pyrimidinyl]-l,3-benzenediamine, aulfate. g. The compound according to Claim If N-(4—(2-(diethylamino)ethoxylpheny11-4-(4-pyridinyl)-2-pyrimidinamine.
8. 10. The compound according to Claim 1/ 4-(lH—indol-3-yl)-N-phenyl-2-pyrimidinamine. -10911. The compound according to Claim 1; N-(4-ethylphenyl )-4-( 4-pyridinyl, -2-pyrimidinamine.
9. 12. The compound according to Claim 1/ N,N—dime thy 1-N*-(4-( 3-pyridinyl)-2-pyr imidinyl ]-l, 4-benzenediamine, trihydrochloride.
10. 13. The compound according to Claim 1/ N-(4— (1 H-imidazol-1-yl )phenyl ]-4-(3-pyridinyl ,-2-pyrimidinam'ine.
11. 14. The compound according to Claim 1/ N-(4T<4-methyl-l-piperazinyl)phenyl J-4-(3-pyridinyl )-2-pyrimidinamine.
12. 15. The compound according to Claim 1; N-(3-.methy1phenyl)-4-(4-pyridinyl)-2-pyr imidinamine.
13. 16. A composition of matter in dosage unit form comprising from about 5 mg to about 1500 mg of a compound of Claim 1 in association with a pharmaceutically acceptable carrier .
14. 17. A process for producing a compound of the formula: wherein Rp R2, R31 R4 and Rg are as defined in claim 1, 110 wnich comprises condensing an alkanoyl-heteroaryl derivative of the formula: O II wherein and are as hereinbefore defined with an j ~ N,K-di(lower alkyl) formamide cr aceramide di (lower o o alkyl)-acetal at 50 -150 C for 4-24 hours to provide a 3-di(lower alkyl)amino acrylophenone of the formula: ?. 3 -C-C=C-N(lower alkyl) 2 which is then cyclized with a substituted phenylguanidine of the formula: EN C-N wherein and R 2 are as hereinbefore defined in an inert organic solvent at the reflux temperature for 6-48 hours.
15. 18. A compound according to claim 1 wherein the compound is: N-(4-Ethylphenyl)-4-(6-methyl-3-pyridinyl) -2-pyrimidinamine ; N-(4-Ethylphenyl)-6-methyl-4(6-methyl-3-pyridinyl)-2-pyrimidin-amine; 111 Κ— (4-Prhylphenyl) -4 (-2-pyrazinyl) -2-pyrimidinamine; N- (3-Methylphenyl)-4-(2-pyrazinyl) -2-pyrimidinamine; N-1 -Naphthaleny 1-4- (4-pyridinyl) -2-pyrimidinamine; N-l-h'3c. r .trialenyl-4- (2-pyridinyl) -2-pyrimidinamine; N-Cyclopentyl-4-(2-pyridinyl) -2-pyrimidinamine; N- Phenyl-4- (4-quinolinyl) -2-primidinamine; N - ?henyl-4- (lH-pyrrol-2-yl) -2-pyrimidinamine ; N- (3-Kathylphenyl) -4-( lH-pyrrol-2-yl) -2-pyrimidinamine; N ,N-Dinethy 1-N' -[4- (3-methyl-2-thienyl) -2-primidinyl]1,4-benzenediamine; N- [4- (2-?yridinyl) -2-pyrimidinyl]-IH -benzir.idazol-2-amine; N-[4-(2-Puranyl) -2-pyrimidinyl]-lH-benzimidozal-2amine; N-(3-Methoxyphenyl) -4-(3-methyl-2-thienyl) -2-pyrimidinamine ; N-[4 -(2-Furanyl) -2-pyrimidi nyl]-IH -benzimidazol-2-amine; or N-(3-Methoxyphenyl) -4- (3-methyl-2-thienyl) -2-pyrimidinamine. - 112
16. 19. A process as claimed in claim 17 substantially as described herein with reference to the Examples.
17. 20. A compound whenever produced by a process as claimed in claim 17 or claim 19.
IE7487A 1986-01-13 1987-01-13 4,5,6-substituted-2-pyrimidinamines IE74202B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US81795186A 1986-01-13 1986-01-13

Publications (2)

Publication Number Publication Date
IE870074L IE870074L (en) 1987-07-13
IE74202B1 true IE74202B1 (en) 1997-07-16

Family

ID=25224278

Family Applications (1)

Application Number Title Priority Date Filing Date
IE7487A IE74202B1 (en) 1986-01-13 1987-01-13 4,5,6-substituted-2-pyrimidinamines

Country Status (18)

Country Link
EP (1) EP0233461B2 (en)
JP (1) JPH0780857B2 (en)
KR (1) KR900004693B1 (en)
AT (1) ATE135699T1 (en)
AU (2) AU591223B2 (en)
BR (1) BR1100989A (en)
CA (1) CA1320201C (en)
DE (1) DE3751742T3 (en)
DK (1) DK171251B1 (en)
ES (1) ES2087056T3 (en)
FI (1) FI91150C (en)
GR (1) GR3019455T3 (en)
HU (1) HU198708B (en)
IE (1) IE74202B1 (en)
NZ (1) NZ218924A (en)
PH (1) PH25056A (en)
SG (1) SG47583A1 (en)
ZA (1) ZA87219B (en)

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4966622A (en) * 1988-04-12 1990-10-30 Ciba-Geigy Corporation N-phenyl-N-pyrimidin-2-ylureas
FR2632521B1 (en) * 1988-06-10 1990-09-14 Rhone Poulenc Sante NOVEL PHENOTHIAZINE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
GB8903592D0 (en) * 1989-02-16 1989-04-05 Boots Co Plc Therapeutic agents
IE62023B1 (en) * 1989-01-02 1994-12-14 Boots Co Plc Therapeutic agents
IN172842B (en) * 1990-05-17 1993-12-11 Boots Pharmaceuticals Limited
CN1037346C (en) * 1990-06-29 1998-02-11 布茨公司 Therapeutic agents
US5270319A (en) * 1991-09-09 1993-12-14 Warner-Lambert Company 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents
US5162328A (en) * 1991-12-31 1992-11-10 American Cyanamid Company N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]-4-(2-thienyl)-2-pyrimidinamine and pharmacologically acceptable salts
US5220025A (en) * 1992-02-24 1993-06-15 Warner-Lambert Company 2-substituted amino-4, 6-di-tertiary-butyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents
US5196431A (en) * 1992-02-24 1993-03-23 Warner-Lambert Company 2-substituted amino-4, 6-di-tertiary-buthyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents
US5521184A (en) * 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
TW225528B (en) * 1992-04-03 1994-06-21 Ciba Geigy Ag
GB9212673D0 (en) * 1992-06-15 1992-07-29 Celltech Ltd Chemical compounds
US5516775A (en) * 1992-08-31 1996-05-14 Ciba-Geigy Corporation Further use of pyrimidine derivatives
GB9222253D0 (en) * 1992-10-23 1992-12-09 Celltech Ltd Chemical compounds
GB9304920D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
GB9304919D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
PL179417B1 (en) * 1993-10-01 2000-09-29 Novartis Ag Pharmacologically active derivatives of pyridine and methods of obtaining them
CA2148931A1 (en) * 1993-10-01 1995-04-13 Jurg Zimmermann Pyrimidineamine derivatives and processes for the preparation thereof
PT672042E (en) * 1993-10-01 2006-08-31 Novartis Ag Pharmacologically active pyrimidineamine derivatives and processes for their preparation
US5543520A (en) * 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives
GB9326600D0 (en) * 1993-12-22 1994-03-02 Celltech Ltd Chemical compounds
ATE260911T1 (en) * 1993-12-22 2004-03-15 Celltech R&D Ltd TRISUBSUTITUTED PHENYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS PHOSPHODIESTERASE (TYPE IV) INHIBITORS
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
GB9412573D0 (en) * 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412571D0 (en) * 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412672D0 (en) * 1994-06-23 1994-08-10 Celltech Ltd Chemical compounds
GB9523675D0 (en) 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
GB9526246D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9526243D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9526245D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
ZA9610687B (en) * 1995-12-22 1997-09-29 Smithkline Beecham Corp Novel synthesis.
US6096748A (en) 1996-03-13 2000-08-01 Smithkline Beecham Corporation Pyrimidine compounds useful in treating cytokine mediated diseases
GB9608435D0 (en) * 1996-04-24 1996-06-26 Celltech Therapeutics Ltd Chemical compounds
GB9619284D0 (en) * 1996-09-16 1996-10-30 Celltech Therapeutics Ltd Chemical compounds
GB9622363D0 (en) * 1996-10-28 1997-01-08 Celltech Therapeutics Ltd Chemical compounds
GB9625184D0 (en) * 1996-12-04 1997-01-22 Celltech Therapeutics Ltd Chemical compounds
JP2001507349A (en) 1996-12-23 2001-06-05 セルテック セラピューティックス リミテッド Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors
GB9705361D0 (en) * 1997-03-14 1997-04-30 Celltech Therapeutics Ltd Chemical compounds
GB9713087D0 (en) * 1997-06-20 1997-08-27 Celltech Therapeutics Ltd Chemical compounds
AU764479B2 (en) * 1998-10-29 2003-08-21 Bristol-Myers Squibb Company Compounds derived from an amine nucleus that are inhibitors of IMPDH enzyme
US6239279B1 (en) 1998-12-16 2001-05-29 Smithkline Beecham Corporation Synthesis for 4-aryl-5-pyrimidine imidazole substituted derivatives
GB9914258D0 (en) 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
US6498165B1 (en) 1999-06-30 2002-12-24 Merck & Co., Inc. Src kinase inhibitor compounds
CA2376951A1 (en) 1999-06-30 2001-01-04 Peter J. Sinclair Src kinase inhibitor compounds
AU6605200A (en) 1999-06-30 2001-01-31 Merck & Co., Inc. Src kinase inhibitor compounds
GB9924862D0 (en) 1999-10-20 1999-12-22 Celltech Therapeutics Ltd Chemical compounds
WO2001060816A1 (en) * 2000-02-17 2001-08-23 Amgen Inc. Kinase inhibitors
EP1274705A1 (en) * 2000-03-29 2003-01-15 Cyclacel Limited 2-substituted 4-heteroaryl-pyrimidines and their use in the treatment of proliferative disorders
US7429599B2 (en) * 2000-12-06 2008-09-30 Signal Pharmaceuticals, Llc Methods for treating or preventing an inflammatory or metabolic condition or inhibiting JNK
US7122544B2 (en) * 2000-12-06 2006-10-17 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
JP4309657B2 (en) * 2001-02-20 2009-08-05 アストラゼネカ・アクチエボラーグ 2-Allylamino-pyrimidine for the treatment of GSK-3-related disorders
GB0107901D0 (en) * 2001-03-29 2001-05-23 Cyclacel Ltd Anti-cancer compounds
WO2003029248A1 (en) 2001-09-28 2003-04-10 Cyclacel Limited N-(4-(4-methylthiazol-5-yl) pyrimidin-2-yl) -n-phenylamines as antiproliferative compounds
MXPA04004176A (en) * 2001-11-01 2004-09-06 Janssen Pharmaceutica Nv AMINOBENZAMIDE DERIVATIVES AS GLYCOGEN SYNTHASE KINASE 3beta INHIBITORS.
EP1448556A1 (en) 2001-11-01 2004-08-25 Janssen Pharmaceutica N.V. Heteroaryl amines as glycogen synthase kinase 3beta inhibitors (gsk3 inhibitors)
TW200302728A (en) 2002-02-01 2003-08-16 Novartis Ag Substituted amines as IgE inhibitors
GB0222514D0 (en) 2002-09-27 2002-11-06 Novartis Ag Organic compounds
GB0229581D0 (en) * 2002-12-19 2003-01-22 Cyclacel Ltd Use
CA2576159A1 (en) 2004-08-27 2006-03-02 Cyclacel Limited Purine and pyrimidine cdk inhibitors and their use for the treatment of autoimmune diseases
CN101115749B (en) 2004-12-17 2011-06-22 安姆根有限公司 Aminopyrimidine compounds and methods of use
GB0500492D0 (en) * 2005-01-11 2005-02-16 Cyclacel Ltd Compound
GB0520958D0 (en) 2005-10-14 2005-11-23 Cyclacel Ltd Compound
WO2007053776A1 (en) * 2005-11-03 2007-05-10 Sgx Pharmaceuticals, Inc. Pyrimidinyl-thiophene kinase modulators
EA200900799A1 (en) * 2006-12-22 2009-12-30 Новартис Аг Heteroarylheteroaryl compounds as inhibitors of CDK, intended for the treatment of cancer, inflammation and the fight against viral infections
ES2535166T3 (en) * 2007-09-04 2015-05-06 The Scripps Research Institute Substituted pyrimidinyl amines as protein kinase inhibitors
AU2009203773B2 (en) 2008-01-11 2013-04-18 F. Hoffmann-La Roche Ag Modulators for amyloid beta
CN101952275B (en) 2008-02-22 2014-06-18 弗·哈夫曼-拉罗切有限公司 Modulators for amyloid protein beta
WO2010040661A1 (en) 2008-10-09 2010-04-15 F. Hoffmann-La Roche Ag Modulators for amyloid beta
EP2355817A1 (en) 2008-11-10 2011-08-17 F. Hoffmann-La Roche AG Heterocyclic gamma secretase modulators
WO2010068863A2 (en) 2008-12-12 2010-06-17 Cystic Fibrosis Foundation Therapeutics, Inc. Pyrimidine compounds and methods of making and using same
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
US8334292B1 (en) 2010-06-14 2012-12-18 Cystic Fibrosis Foundation Therapeutics, Inc. Pyrimidine compounds and methods of making and using same
WO2013035102A1 (en) 2011-09-05 2013-03-14 Natco Pharma Limited Processes for the preparation of imatinib base and intermediates thereof
RU2486180C1 (en) * 2011-11-02 2013-06-27 Общество с ограниченной ответственностью "ТехноХим" (ООО "ТехноХим") Method for preparing 2-arylamino-4-hetarylpyrimidines
WO2014055972A2 (en) * 2012-10-05 2014-04-10 The Regents Of The University Of California A new chemical entity useful for treating various diseases
CN114181199B (en) * 2020-09-15 2023-09-26 成都赜灵生物医药科技有限公司 2, 4-disubstituted pyrimidine derivative, preparation method and application thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB735702A (en) * 1952-03-18 1955-08-24 Wellcome Found Improvements in and relating to 2,4-diaminopyrimidines and methods of making the same
US4512993A (en) * 1983-07-25 1985-04-23 Sterling Drug Inc. 4(Or 5)-(pyridinyl)-2-pyrimidinamines and cardiotonic use thereof
US4504482A (en) * 1983-07-28 1985-03-12 Sterling Drug Inc. [5(or 4)-(Pyridinyl)-2-pyrimidinyl]ureas and cardiotonic use thereof
EP0164204A1 (en) † 1984-05-12 1985-12-11 FISONS plc Novel pharmaceutically useful pyrimidines
GB8412184D0 (en) * 1984-05-12 1984-06-20 Fisons Plc Biologically active nitrogen heterocycles
US4725600A (en) † 1984-07-13 1988-02-16 Fujisawa Pharmaceutical Co., Ltd. Pyrimidine compounds having activity as a cardiotonic anti-hypertensive cerebrovascular vasodilator and anti-platelet aggregation agent
WO1986004583A1 (en) * 1985-02-05 1986-08-14 The Upjohn Company 4-substituted-6-aryl pyrimidine compounds
US4711888A (en) * 1985-07-24 1987-12-08 Pfizer Inc. Hydroxy and alkoxy pyrimidines

Also Published As

Publication number Publication date
ATE135699T1 (en) 1996-04-15
FI91150C (en) 1994-05-25
DK171251B1 (en) 1996-08-12
AU5057890A (en) 1990-07-26
HU198708B (en) 1989-11-28
NZ218924A (en) 1990-04-26
DE3751742T2 (en) 1996-11-21
EP0233461B1 (en) 1996-03-20
HUT43582A (en) 1987-11-30
BR1100989A (en) 1999-11-09
JPH0780857B2 (en) 1995-08-30
AU591223B2 (en) 1989-11-30
ZA87219B (en) 1987-08-26
KR870007154A (en) 1987-08-17
EP0233461A3 (en) 1988-05-25
PH25056A (en) 1991-01-28
FI91150B (en) 1994-02-15
SG47583A1 (en) 1998-04-17
DE3751742D1 (en) 1996-04-25
DK15187D0 (en) 1987-01-13
AU621461B2 (en) 1992-03-12
KR900004693B1 (en) 1990-07-02
EP0233461B2 (en) 2002-05-29
EP0233461A2 (en) 1987-08-26
AU6751887A (en) 1987-07-16
JPS62223177A (en) 1987-10-01
ES2087056T3 (en) 1996-07-16
DK15187A (en) 1987-07-14
FI870113A0 (en) 1987-01-13
DE3751742T3 (en) 2002-11-21
CA1320201C (en) 1993-07-13
FI870113A (en) 1987-07-14
GR3019455T3 (en) 1996-06-30
IE870074L (en) 1987-07-13

Similar Documents

Publication Publication Date Title
IE74202B1 (en) 4,5,6-substituted-2-pyrimidinamines
US4788195A (en) 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines
US4876252A (en) 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines
US6506747B1 (en) Substituted 1-(4-aminophenyl)pyrazoles and their use as anti-inflammatory agents
US6093735A (en) Selective β-3 adrenergic agonists
KR101066501B1 (en) Substituted piperazines
RU2274639C2 (en) Derivatives of substituted triazoldiamine, pharmaceutical composition based on thereof and method for its preparing
EP0934307B1 (en) Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase
US6075040A (en) Selective β3 adrenergic agonists
US7115645B2 (en) 1,2 diarylbenzimidazoles and their pharmaceutical use
US6028202A (en) 1,5-diarylpyrazoles
CZ200036A3 (en) Triazole compounds and their use
JP2003500357A (en) Antibacterial compound
KR20170072957A (en) Pyrazole derivatives as modulators of calcium release -activated calcium channel
Paul et al. Preparation of substituted N-phenyl-4-aryl-2-pyrimidinamines as mediator release inhibitors
PT86573B (en) PROCESS FOR THE PREPARATION OF INDAZOLE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
KR100703908B1 (en) 1,2-diaryl benzimidazoles for treating illnesses associated with a microglia activation
WO2007121687A1 (en) 4-methyl-1h-diaryl pyrazole derivatives and their uses as medicament
US6046227A (en) Selective β3 adrenergic agonists
DK151017B (en) METHOD OF ANALOGUE FOR PREPARING SUBSTITUTED N- (4-INDOLYL-PIPERIDINO-ALKYL) -BENZIMIDAZOLONES OR PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF
WO2007104696A1 (en) Antimalarial agents having polyaromatic structure
US7345075B2 (en) 1,2 diarylbenzimidazoles and their pharmaceutical use
RU2497811C2 (en) Phenylimidazole compounds
KR100683418B1 (en) Thiourea and isothiourea derivatives for inhibiting ras-transformed cell growth
KR20150046456A (en) Novel antifungal oxodihydropyridinecarbohydrazide derivatives

Legal Events

Date Code Title Description
MM4A Patent lapsed